title: Anti-platelet drug resistance in the prediction of thromboembolic complications after neurointervention. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Evaluation of the Quality of Prognosis Studies in Systematic Reviews 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 Association of Cyclooxygenase-1–Dependent and –Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease Clopidogrel for Coronary Stenting Response Variability, Drug Resistance, and the Effect of Pretreatment Platelet Reactivity Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance. Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function. Biological efficacy of low against medium dose aspirin regimen after coronary surgery: analysis of platelet function. Aspirin Responsiveness in Acute Brain Ischaemia: Association with Stroke Severity and Clinical Outcome Comparison of 2 point-of-care platelet function tests, VerifyNow Assay and Multiple Electrode Platelet Aggregometry, for predicting early clinical outcomes in patients undergoing percutaneous coronary intervention. Aspirin resistance determined with PFA-100 does not predict new thrombotic events in patients with stable ischemic cerebrovascular disease A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Abnormal PFA-100 closure time is associated with increased platelet aggregation in patients presenting with chest pain Serial Urinary 11-Dehydrothromboxane B2, Aspirin Dose, and Vascular Events in Blacks After Recent Cerebral Infarction A population-based study of peripheral arterial disease prevalence with special focus on critical limb ischemia and sex differences. The contribution of cyclooxygenase-1 and -2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug-eluting stents. Reporting of prognostic markers: current problems and development of guidelines for evidence-based practice in the future Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin Screening for Aspirin Responsiveness After Transient Ischemic Attack and Stroke: Comparison of 2 Point-of-Care Platelet Function Tests With Optical Aggregometry Bedside monitoring to adjust antiplatelet therapy for coronary stenting. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: a 6 months prospective study. Variability of non-response to aspirin in patients with peripheral arterial occlusive disease during long-term follow-up Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications. Effects of persistent platelet reactivity despite aspirin therapy on cardiac troponin I and creatine kinase-MB levels after elective percutaneous coronary interventions Risk stratification after coronary artery bypass surgery by a point-of-care test of platelet function. Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and female volunteers. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. The effects of aspirin and clopidogrel response on myonecrosis after percutaneous coronary intervention: a BRIEF-PCI (Brief Infusion of Intravenous Eptifibatide Following Successful Percutaneous Coronary Intervention) trial substudy. Aspirin resistance measured by cationic propyl gallate platelet aggregometry and recurrent cardiovascular events during 4 years of follow-up. Preoperative Aspirin Resistance does not Increase Myocardial Injury during Off-pump Coronary Artery Bypass Surgery Beneficial Effects of Clopidogrel Combined With Aspirin in Reducing Cerebral Emboli in Patients Undergoing Carotid Endarterectomy Protocol for a systematic review of the diagnostic and prognostic utility of tests currently available for the detection of aspirin resistance in patients with established cardiovascular or cerebrovascular disease High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention Platelet function in patients with acute coronary syndrome (ACS) predicts recurrent ACS. High on-treatment platelet reactivity by more than one agonist predicts 12-month follow-up cardiovascular death and non-fatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting. Results of the BRAT study--a pilot study investigating the possible significance of ASA nonresponsiveness on the benefits and risks of ASA on thrombosis in patients undergoing coronary artery bypass surgery. Aspirin resistance in secondary stroke prevention Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Dichotomizing continuous predictors in multiple regression: a bad idea. Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR) Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. Earlier application of loading doses of aspirin and clopidogrel decreases rate of recurrent cardiovascular ischemic events for patients undergoing percutaneous coronary intervention. Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease The Effect of Aspirin Dosing on Platelet Function in Diabetic and Nondiabetic Patients Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. Association of recurrent cerebral infarction with adenosine diphosphate- and collagen-induced platelet aggregation in patients treated with ticlopidine and/or aspirin. Relation of aspirin resistance to coronary flow reserve in patients undergoing elective percutaneous coronary intervention. [Study on the relationship between aspirin resistance and incidence of myonecrosis after non-emergent percutaneous coronary intervention]. Prediction of the excessive perioperative bleeding in patients undergoing coronary artery bypass grafting: role of aspirin and platelet glycoprotein IIIa polymorphism. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. 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. The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis. Prehospital triple antiplatelet therapy in patients with acute ST elevation myocardial infarction leads to better platelet aggregation inhibition and clinical outcome than dual antiplatelet therapy Prospective, observational study of antiplatelet and coagulation biomarkers as predictors of thromboembolic events after implantation of ventricular assist devices Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in Stent Thrombosis (CREST) registry Guidance of anticoagulation after intracoronary implantation of Palmaz-Schatz stents by monitoring prothrombin and prothrombin fragment 1 + 2. Prospective evaluation of the relationship between platelet–leukocyte conjugate formation and recurrent myocardial ischemia in patients with acute coronary syndromes Efficacy of predicting thrombotic events with combination of dual point-of-care testing (POCT) after drug-eluting stent implantation for coronary heart disease: results from the CILON-T randomized trial POCT substudy. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. The impact of oral antiplatelet responsiveness on the long-term prognosis after coronary stenting. The effect of acetylsalicylic acid resistance on prognosis of patients who have developed acute coronary syndrome during acetylsalicylic acid therapy. The Economic Burden of Stroke in the United Kingdom Addition of cilostazol reduces biological aspirin resistance in aspirin users with ischaemic stroke: a double-blind randomized clinical trial. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers. Aspirin resistance in Indian patients with coronary artery disease and cardiovascular events. Heterogeneity in platelet cyclooxygenase inhibition by aspirin in coronary artery disease. Thienopyridine Therapy Influences Late Outcome After Coronary Stent Implantation Prognostic value of in vitro measurements of platelet aggregability and fibrinolytic activity in patients with reversible cerebral ischemic attacks. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin "resistance". Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: A potential antiplatelet therapeutic target Prevalence of platelet nonresponsiveness to aspirin in patients treated for secondary stroke prophylaxis and in patients with recurrent ischemic events.
abstract: OBJECTIVE The aim of this study was to analyze the correlation between thromboembolic complications and antiplatelet drugs before and after neurointervention . METHODS Blood sample s and radiographic data of patients who received a neurointervention ( coil embolization , stent placement or both )  were collected prospect ively . Rapid platelet function assay-aspirin ( RPFA-ASA ) was used to calculate aspirin resistance in aspirin reaction units ( ARU ) . For clopidogrel resistance , a P2Y12 assay was used to analyze the percentage of platelet inhibition . ARU > 550 and platelet inhibition < 40 % were defined as aspirin and clopidogrel resistance , respectively . RESULTS Both aspirin and clopidogrel oral pills were administered in fifty-three patients before and after neurointerventional procedures . The mean resistance values of all patients were 484 ARU and < 39 % . Ten ( 17.0 % ) of 53 patients showed resistance to aspirin  with an average of 597 ARU , and 33 ( 62.3 % ) of 53 patients showed resistance to clopidogrel  with an average of < 26 % . Ten patients demonstrated resistance to both drugs , 5 of which suffered a thromboembolic complication after neurointervention ( mean values : 640 ARU and platelet inhibition < 23 % ) . Diabetic patients and patients with hypercholesterolemia displayed mean aspirin resistances of 513.7 and 501.8 ARU , and mean clopidogrel resistances of < 33.8 % and < 40.7 % , respectively . CONCLUSION Identifying individuals with poor platelet inhibition using st and ard regimens is of great clinical importance and may help prevent cerebral ischemic events in the future . Neurointerventional research should focus on ideal doses , timing , choices , safety , and reliable measurements of antiplatelet drug therapy , as well as confirming the clinical relevance of aggregometry in cerebrovascular patients Essential thrombocythemia ( ET ) is characterized by enhanced platelet generation and thrombotic complications . Once-daily low-dose aspirin incompletely inhibits platelet thromboxane A(2 ) ( TXA(2 ) ) in the majority of ET patients . In the present study , we investigated the determinants of aspirin-insensitive platelet TXA(2 ) bio synthesis and whether it could be further suppressed by changing the aspirin dose , formulation , or dosing interval . In 41 aspirin-treated ET patients , the immature platelet count predicted serum TXB(2 ) independently of platelet count , age , JAK-2 V617F mutation , or cytoreduction ( β = 3.53 , P = .001 ) . Twenty-one aspirin-treated patients with serum TXB(2 ) ≥ 4 ng/mL at 24 hours after dosing were r and omized to the following 7-day regimens in a crossover design : enteric-coated aspirin 100 mg twice daily , enteric-coated aspirin 200 mg once daily , or plain aspirin 100 mg once daily . A twice-daily regimen caused a further 88 % median ( IQR , 78%-92 % , P < .001 ) TXB(2 ) reduction and normalized the functional platelet response  to  aspirin , as assessed by urinary 11-dehydro-TXB(2 ) excretion and the VerifyNow Aspirin assay . Doubling the aspirin dose reduced serum TXB(2 ) only partially by 39 % median ( IQR , 29%-54 % , P < .05 ) . We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorter-lasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1 , and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items 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 — Poor clinical outcome in  aspirin-treated patients has been termed aspirin resistance and may result from inadequate inhibition of platelet cyclooxygenase-1 ( COX-1 ) by aspirin . The objectives of this study were to determine prospect ively whether COX-1–dependent and other platelet function assays correlate with clinical outcomes in aspirin-treated patients . Methods and Results — Blood was collected before percutaneous coronary intervention from 700 consecutive aspirin-treated ( 81 or 325 mg for ≥3 days ) patients . Platelet function was tested by ( 1 ) serum thromboxane B2 ; ( 2 ) arachidonic acid – stimulated platelet surface P-selectin and activated glycoprotein IIb/IIIa and leukocyte – platelet aggregates ; and ( 3 ) platelet function analyzer (PFA)-100 collagen-epinephrine and collagen-ADP closure time ( CT ) . Adverse clinical outcomes of all-cause death , cardiovascular death , and major adverse cardiovascular events ( cardiovascular death , myocardial infa rct ion , hospitalization for revascularization , or acute coronary syndrome ) were assessed by telephone interview and /or medical record review . Clinical outcomes information was obtained at 24.8±0.3 months after platelet function testing . By univariate analysis , COX-1–dependent assays , including serum thromboxane B2 level , were not associated with adverse clinical outcomes , whereas the COX-1–independent assay , PFA-100 collagen-ADP CT < 65 seconds , was associated with major adverse cardiovascular events ( P=0.0149 ) . After adjustment for covariables ( including sex , aspirin dose , Thrombolysis in Myocardial Infa rct ion risk score , clopidogrel use ) , both serum thromboxane B2 > 3.1 ng/mL and PFA-100 collagen-ADP CT < 65 seconds were associated with major adverse cardiovascular events . In contrast , indirect measures of platelet COX-1 ( arachidonic acid – stimulated platelet markers , shortened PFA-100 collagen-epinephrine CT ) were not significantly associated with adverse clinical outcomes even after adjustment for covariables . Conclusions — In this prospect i ve study of 700 aspirin-treated patients presenting for angiographic evaluation of coronary artery disease , residual platelet COX-1 function measured by serum thromboxane B2 and COX-1–independent platelet function measured by PFA-100 collagen-ADP CT , but not indirect COX-1–dependent assays ( arachidonic acid – stimulated platelet markers , shortened PFA-100 collagen-epinephrine CT ) , correlate with subsequent major adverse cardiovascular events . This study suggests that multiple mechanisms , including but not confined to inadequate inhibition of COX-1 , are responsible for poor clinical outcomes in aspirin-treated patients , and therefore the term aspirin resistance is inappropriate Background — Patients with type 2 diabetes mellitus ( T2DM ) have reduced aspirin-induced pharmacodynamic effects . This may be attributed to increased platelet turnover rates result ing in an increased proportion of non – aspirin-inhibited platelets during the daily dosing interval . The hypothesis of this study was that an increase in the frequency of drug administration [ twice daily ( bid ) versus once daily ( od ) ] may provide more effective platelet inhibition in T2DM patients . Methods and Results — T2DM patients with stable coronary artery disease were prospect ively recruited . Patients modified their aspirin regimen on a weekly basis according to the following scheme : 81 mg/od , 81 mg/bid , 162 mg/od , 162 mg/bid , and 325 mg/od . Pharmacodynamic assessment s included light-transmittance aggregometry after arachidonic acid , collagen and adenosine diphosphate stimuli ; VerifyNow-Aspirin assay ; and serum thromboxane B2 ( TXB2 ) levels .  Twenty patients were analyzed . All patients were sensitive and compliant to aspirin irrespective of dose , as assessed by arachidonic acid – induced aggregation . When aspirin was administered once daily , there was no significant effect on platelet reactivity by increasing the once-daily dosing using aspirin-sensitive assays ( collagen-induced aggregation and VerifyNow-Aspirin ) . An increase in aspirin dose by means of a second daily administration was associated with a significant reduction in platelet reactivity assessed by collagen-induced aggregation and VerifyNow-Aspirin between 81 mg/od and 81 mg/bid ( P<0.05 for both assays ) and between 81 mg/od and 162 mg/bid ( P<0.05 for both assays ) . There was no impact of aspirin dosing regimens on adenosine diphosphate – induced aggregation . A dose-dependent effect of aspirin was observed on serum TXB2 levels ( P=0.003 ) . Conclusions — Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable coronary artery disease , with a twice-daily , low-dose aspirin administration result ing in greater platelet inhibition than once-daily administration as assessed by aspirin-sensitive assays and a dose-dependent effect on serum TXB2 levels . The clinical implication s of a modified aspirin regimen tailored to T2DM patients warrant further investigation . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01201785 Background Clopidogrel is administered to prevent stent thrombosis ; however , the uniformity of platelet inhibition after treatment and the influence of pretreatment reactivity on drug response have not been described . Methods and Results Platelet aggregation ( 5 and 20 μmol/L ADP ) , the activation of glycoprotein IIb/IIIa ( PAC‐1 antibody ) , and the expression of P‐selectin were measured in patients undergoing elective coronary stenting ( n=96 ) at baseline and at 2 hours , 24 hours , 5 days , and 30 days after stenting . All patients received aspirin ( 325 mg ) . Clopidogrel ( 300 mg ) was administered in the catheterization laboratory and followed by 75 mg daily . There was marked interindividual variability in drug response as measured by all markers that showed a normal distribution . Resistance , defined as baseline aggregation ( % ) minus posttreatment aggregation ( % ) ≤10 % by 5 μmol/L ADP , was present in 31 % and 15 % of patients at 5 and 30 days , respectively . Patients with the highest pretreatment platelet reactivity remained the most reactive at 24 hours after treatment ( P<0.0001 ) . Conclusions Interindividual variability in the platelet inhibitory response  from clopidogrel occurs in patients undergoing elective coronary stenting . Patients with high pretreatment reactivity are least protected . Alternative pharmacological strategies and the association of adverse ischemic events should be investigated in these patients . ( Circulation . 2003 ; 107:2908‐2913 . BACKGROUND Late venous graft thrombosis , leading to recurrent ischemia , is frequently encountered in old , degenerated vein grafts with advanced atherosclerotic plaque formation . Aspirin has been indicated to maintain venous graft patency in the post-operative period . However , there is considerable evidence that aspirin resistance is of concern in patients with venous grafts . MATERIAL AND METHOD Prospect ively enrolled 14 patients ( 11 male , 3 female , Group 1 ) , who were shown to have at least one occluded saphenous vein graft on their late control coronary angiogram after bypass operation , were compared for the presence of aspirin resistance by PFA-100 with age- and sex-matched 14 patients ( 10 male , 4 female , Group 2 ) , who were found patent and well-functioning vein grafts without wall irregularities on late post-operative coronary angiograms ( mean 6.5+/-2.5 years ) , enrolled as a control group . RESULTS Mean CT of collagen/epinephrine cartridge in Group 1 was 197+/-85 s and significantly less than in Group 2 ( 279+/-44 s ; p=0.011 ) . It was found that 50 % of patients in Group 1 were so-called aspirin resistant , whereas in Group 2 , this ratio was 7.1 % ( p=0.033 ) . BMI ( p=0.038 , Beta=-0.322 ) , uric acid level ( p=0.023 , Beta=-0.355 ) , and CT by collagen/epinephrine cartridge ( p=0.008 , Beta=0.431 ) were independently predicting late occlusion of saphenous vein graft . CONCLUSION Aspirin resistance is highly prevalent in patients with occluded venous grafts at a relatively late period 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 A higher rate of clinical events in poor clopidogrel and /or aspirin responders was documented by using different methods to measure platelet function , but no conclusive data about the appropriate methodology to explore platelet reactivity are available . A total of 746 patients included in the cohort of the RECLOSE trial who had successful drug-eluting stent implantation were assessed for post-treatment residual platelet reactivity ( RPR ) in platelet-rich plasma by 10 microM adenosine 5'-diphosphate ( ADP ) , 1 mM arachidonic acid ( AA ) and 2 microg/ml collagen-induced platelet aggregation and in whole blood by the PFA-100 system . At six-month follow-up , RPR by two stimuli ( ADP and AA or ADP and collagen ) and by three stimuli ( ADP , AA and collagen ) is significantly associated with higher percentage of primary ( definite or probable stent thrombosis ) and secondary ( cardiac mortality and stent thrombosis ) end-points than RPR by ADP , AA , collagen and PFA-100 system . According to the primary and secondary end points , the specificity values for RPR identified by two ( ADP and AA:94 % ; ADP and collagen:97 % ) and three stimuli were higher with respect to RPR by ADP ( 88 % ) , or RPR by AA ( 83 % ) or RPR by collagen ( 90 % ) . The positive likelihood ratio values of RPR by three stimuli ( 9.55 ) or of RPR by ADP and collagen ( 8.08 ) were higher than those of RPR by ADP ( 2.59 ) , by AA ( 2.05 ) , by collagen ( 4.73 ) , or by PFA-100 ( 2.63 ) . This prospect i ve study documents that the evaluation of platelet reactivity addressed to identify patients at risk of thrombotic events on dual antiplatelet treatment has to be carried out by methods able to explore different pathways The failure of aspirin to inhibit platelet function has been documented in patients undergoing coronary artery bypass graft ( CABG ) surgery , but the causes of " aspirin-resistance " remain uncertain . The aim of this study was to investigate the efficacy of aspirin in patients undergoing CABG surgery receiving either 100 mg or 325 mg of oral aspirin for 5-days . Platelet function was tested the day before surgery and on day + 1 and day + 5 , and evaluated by changes in collagen-induced thromboxane-A2 ( TxA2 ) release and platelet aggregation following stimulation with collagen , ADP and epinephrine . In all patients , baseline platelet aggregation was significantly inhibited by pre-incubation with in vitro aspirin ( 150 micromol/l ) , with a mean reduction in TxA2-release of > or=95.5 % ( 82.3,99.1 ) . After 5-days of oral aspirin , platelet aggregation was significantly inhibited , and was not further inhibited by in vitro aspirin . Oral aspirin was also associated with a > or=99.5 % ( 97.8 , 99.7 ) reduction in TxA2-release , and with the reversal of the second-phase of ADP-induced aggregation which is TxA2-dependent . In addition a single-dose of 325 mg aspirin on the first post-operative morning may have a greater inhibitory effect on collagen-induced aggregation than 100 mg aspirin . Western blot analysis provided no evidence for the presence of COX-2 in platelets , while the up-regulation of p38-MAPK following platelet-stimulation and surgery was seen . The inhibition of COX-2 ( NS398 ) or p38-MAPK ( SB203580 ) activity did not affect platelet aggregation and TxA2-release on day + 5 . In summary , there was no evidence for inherent or acquired aspirin-resistance in this surgical population , or for the involvement of either COX-2 or p38-MAPK Purpose : Platelets play a critical role in the pathogenesis of acute brain ischaemia . We studied the association between the degree of inhibition of platelet function by aspirin ( ASA ) and the severity and outcome of acute brain ischaemia . Methods : Platelet responsiveness to ASA was assessed in patients with acute brain ischaemia , treated with ASA since hospital admission . The degree of ASA responsiveness was assessed by optical aggregometry and categorized into patients with good response , partial response and complete unresponsiveness to ASA ( good responders , partial responders and non-responders , respectively ) . An additional evaluation of responsiveness to ASA was performed by Impact-R ( cone and platelet analyzer ) . Patients underwent serial clinical assessment during hospitalization , at discharge and during follow-up . Results : Among 105 patients ( mean age 63 ± 12 years ; 66 % men ) , impaired ASA responsiveness at baseline as assessed by aggregometry was associated with increased stroke severity at baseline , unfavourable clinical course , and poor functional outcome during follow-up ( p < 0.05 for all ) . Age-adjusted odds ratios in non-responders compared to good responders were 9.8 for severe stroke on admission ( 95 % CI 2.8–34.9 ) , 3.1 for lack of early clinical improvement ( 95 % CI 1.1–8.8 ) and 8.6 for poor functional outcome during follow-up ( 95 % CI 2.4–30.4 ) . Less robust trends were observed with the Impact-R. Conclusions : Impaired responsiveness to ASA in acute brain ischaemia is common and is associated with worse neurological deficits at stroke onset , early clinical deterioration and poorer functional outcome . The clinical significance of these findings requires further evaluation in larger longitudinal studies BACKGROUND Various platelet function tests are currently used to measure responsiveness to antiplatelet therapy . We sought to compare 2 point-of-care platelet function tests , VerifyNow Assay ( Accumetrics , San Diego , CA ) and Multiple Electrode Platelet Aggregometry ( MEA ) ( Dynabyte , Munich , Germany ) , for predicting early clinical outcomes after percutaneous coronary intervention . METHODS Platelet reactivity in the arachidonic acid-induced and adenosine diphosphate (ADP)-induced platelet aggregation was measured simultaneously with the VerifyNow Assay and MEA in 222 patients undergoing percutaneous coronary intervention between August and October 2009 . We investigated the correlations between the 2 tests and performed receiver operating characteristic curve analysis for major adverse cardiovascular events ( MACE ) , a composite of death , myocardial infa rct ion ( MI ) , stroke , and target vessel revascularization , at 30 days . RESULTS Major adverse cardiovascular events occurred in 19 patients ( 8.6 % ) , including 14 patients with periprocedural MI and 5 patients with stroke . Correlations were weak between the 2 tests in the arachidonic acid-induced ( Spearman r = 0.189 , P = .006 ) and ADP-induced platelet reactivity ( Spearman r = 0.390 , P < .001 ) . Although the VerifyNow P2Y12 Assay ( Accumetrics ) was able to predict periprocedural MI ( area under the aggregation curve 0.680 , P = .024 ) and 30-day MACE ( area under the aggregation curve 0.649 , P = .032 ) , VerifyNow Aspirin Assay ( Accumetrics ) , MEA ASPI test , and MEA ADP test failed to predict such clinical events . Hyporesponsiveness to clopidogrel based on the VerifyNow Assay was associated with about a 6-fold increased risk of MACE at 30 days . CONCLUSIONS Hyporesponsiveness to clopidogrel measured by VerifyNow Assay was able to identify patients with dual antiplatelet therapy who were at higher risk for periprocedural MI and MACE at 30 days . Further r and omized studies are required to vali date the effectiveness of different platelet function tests for predicting long-term clinical outcomes OBJECTIVE Evidence is growing that some patients are not responsive to the antithrombotic action of aspirin . We prospect ively evaluated the ability of aspirin resistance status , determined by PFA-100 , to predict new thrombotic events in patients with stable ischemic cerebrovascular disease . METHODS We studied 129 consecutive patients with stroke , transient ischemic attack ( TIA ) or vascular cognitive impairment . We assessed relationships between aspirin resistance , risk factors for ischemic cerebrovascular disease , and occurrence of new thrombotic events ( composite of stroke , TIA , myocardial infa rct ion , and cardiovascular death ) . RESULTS Aspirin resistance , found in 26 ( 20.1 % ) cases , was unrelated to any of the examined vascular risk factors . During mean follow-up of 56 months , new thrombotic events occurred in 19 patients ( 14.7 % ) , four with aspirin resistance ( 15.4 % ) and 15 ( 14.6 % ) without aspirin resistance ( p=1.00 ) . CONCLUSION Aspirin resistance determined by PFA-100 does not predict new thrombotic events in patients with stable ischemic cerebrovascular disease OBJECTIVES This study was design ed to determine if aspirin resistance is associated with clinical events . BACKGROUND Aspirin resistance , defined by platelet function testing and presumed clinical unresponsiveness to aspirin , has been previously reported by our group and others . However , little information exists linking the laboratory documentation of aspirin resistance and long-term clinical events . METHODS We prospect ively enrolled 326 stable cardiovascular patients from 1997 to 1999 on aspirin ( 325 mg/day for > or = 7 days ) and no other antiplatelet agents .  We tested for aspirin sensitivity by optical platelet aggregation using adenosine diphosphate ( ADP ) and arachidonic acid ( AA ) . The primary outcome was the composite of death , myocardial infa rct ion ( MI ) , or cerebrovascular accident ( CVA ) . Mean follow-up was 679 + /- 185 days . Aspirin resistance was defined as a mean aggregation of > or = 70 % with 10 microM ADP and > or = 20 % with 0.5 mg/ml AA . RESULTS Of the patients studied , 17 ( 5.2 % ) were aspirin resistant and 309 ( 94.8 % ) were not aspirin resistant . During follow-up , aspirin resistance was associated with an increased risk of death , MI , or CVA compared with patients who were aspirin sensitive ( 24 % vs. 10 % , hazard ratio [ HR ] 3.12 , 95 % confidence interval [ CI ] 1.10 to 8.90 , p = 0.03 ) . Stratified multivariate analyses identified platelet count , age , heart failure , and aspirin resistance to be independently associated with major adverse long-term outcomes ( HR for aspirin resistance 4.14 , 95 % CI 1.42 to 12.06 , p = 0.009 ) . CONCLUSIONS This study demonstrates the natural history of aspirin resistance in a stable population , documenting a greater than threefold increase in the risk of major adverse events associated with aspirin resistance Recently , great interest has focused on the phenomenon of aspirin resistance , which may be defined as clinical or laboratory resistance . Monitoring the antiplatelet effect appears to be relevant in the presence of clinical implication s , but no data are available on the possible clinical implication s of the failure of aspirin to inhibit tests of platelet function in the setting of acute coronary syndromes . This study evaluated the role of aspirin resistance in the occurrence of 1-year major adverse coronary events ( MACEs ) in patients with acute myocardial infa rct ion ( AMI ) who have undergone percutaneous coronary intervention ( PCI ) . We prospect ively evaluated 146 patients ( 115 men and 31 women ; median age 65 years , range 30 to 84 ) with AMI who underwent primary PCI . Exclusion criteria were the use of glycoprotein IIb/IIIa inhibitors , hematocrit < or=30 % , and a platelet count < 100,000/mm3 . Platelet function analyzer-100 closure times by collagen-epinephrine were used for measuring platelet function in venous blood sample s obtained 12 to 15 hours after revascularization . Patients were considered aspirin resistant in the presence of a collagen-epinephrine closure time of < 203 seconds . After 1-year follow-up , MACEs were recorded in 44 of 146 patients ( 30.1 % ) . A significantly higher percentage of patients with MACEs had aspirin resistance ( 39.1 % vs 23.2 % , p < 0.05 ) . A Kaplan-Meier survival curve showed that the overall risk of MACEs was significantly higher among patients with aspirin resistance ( p = 0.02 ) . A Cox regression analysis that adjusted for age , gender , traditional cardiovascular risk factors , systolic left ventricular function , number of stenosed coronary arteries , and previous AMI , PCI , or coronary artery bypass graft showed aspirin resistance to be a significant and independent risk factor for the future MACEs ( hazard ratio 2.9 , 95 % confidence interval 1.1 to 9.2 , p < 0.05 ) . In conclusion , our data demonstrate that aspirin resistance after PCI is a significant and independent predictor of MACEs in patients with AMI undergoing primary PCI Background Antiplatelet therapy has been proven to be effective for both primary and secondary prevention of myocardial infa rct ion , stroke , and cardiovascular death . However , a significant proportion of patients treated  with aspirin  experience ischemic events . A number of prospect i ve studies have demonstrated that decreased responsiveness to antiplatelet therapy as measured by various methods , is strongly associated with an increase in clinical events . Our objective was to characterize platelet function in patients presenting with chest pain using a point-of-care assay , PFA-100 ® and correlating results to traditional platelet aggregometry to determine if patients with aspirin non-responsiveness have increased clinical sequelae . Methods Platelet function was assessed using PFA-100 ® , flow cytometry , and optical aggregometry in 94 patients presenting to the emergency department with chest pain . All patients were on aspirin 81–325 mg daily . Clinical events occurring during the index hospitalization were documented . Results Forty-seven patients ( 50 % ) were defined as aspirin non-responders by PFA-100 ® ( collagen-epinephrine closure time ≤ 193 ) . Compared to aspirin responders , aspirin non-responders had higher levels of mean platelet aggregation to adenosine diphosphate ( ADP ) ( P = 0.004 ) and high dose epinephrine ( P = 0.03 ) . Furthermore , expression of PAC-1 was significantly increased in patients with aspirin nonresponse as compared to aspirin responders ( P = 0.003 and P = 0.0006 respectively ) . No significant difference in clinical events during the index hospitalization was noted between aspirin non-responders and aspirin responders . Conclusion Patients presenting with chest pain who have abnormal PFA-100 closure times have increased platelet aggregation and activation however this aspirin non-responsiveness does not correlate with increased clinical events in the index hospitalization Background and Purpose — Incomplete platelet inhibition by aspirin ( aspirin resistance ) may be a reason for stroke recurrence in some patients . 11-Dehydrothromboxane B2 ( 11-DTB2 ) is a stable thromboxane A2 metabolite that reflects in vivo platelet activation . This pilot study was intended to evaluate the reproducibility of urinary 11-DTB2 over time and to look for evidence of aspirin resistance . Methods — All subjects were screened for the African American Antiplatelet Stroke Prevention Study ( AAASPS ) 7 to 90 days after noncardioembolic cerebral infa rct ion . Of 83 subjects with at least 1 urine sample , 52 were enrolled in AAASPS ( r and omized to blinded treatment with aspirin 650 mg/d or ticlopidine 500 mg/d ) , and 31 were enrolled in an open-label antiplatelet therapy cohort .  Subjects were followed up for 2 years , with 11-DTB2 measurements scheduled at baseline and 6 , 12 , and 24 months . Vascular events were cerebral infa rct ion , myocardial infa rct ion , or vascular death . Results — Despite considerable individual up or down fluctuations , the median 11-DTB2 change did not significantly differ from zero in any of the subgroups . However , in 6 subjects with a 4-fold decrease in aspirin dose from 1300 to 325 or 81 mg/d , the 11-DTB2 level increased from 611 to 1881 pg/mg creatinine ( P = 0.06 ) . Vascular events occurred in 7 of 61 aspirin-treated subjects , and 11-DTB2 levels did not correlate with the events . Conclusions — Fluctuations in urinary 11-DTB2 after cerebral infa rct ion in blacks do not correlate with changes in aspirin doses , except perhaps when the dose changes by a factor of 4 or more . A larger study is needed to look further for aspirin resistance OBJECTIVE A population -based point-prevalence study was conducted to determine the prevalence of peripheral arterial disease ( PAD ) in Sweden , with special attention to critical limb ischemia and sex differences . METHODS An age-st and ardized r and omly selected population sample of 8000 women and men , aged 60 to 90 years , from four different regions in Sweden was invited to participate . The sample had the same age and gender distribution as the Swedish population in this age group . Participating subjects completed question naires on medical history , present medication , and symptoms , and their ankle-brachial index ( ABI ) was measured . Subjects were analyzed for presence of PAD according to reported symptoms and an ABI<0.9 . RESULTS A total of 5080 subjects were included , giving a participation rate of 64 % . The prevalence of any PAD , asymptomatic PAD , intermittent claudication , and severe limb ischemia was , respectively , 18 % ( 95 % confidence interval [ CI ] , 16 % to 20 % ) 11 % ( 9 % to 13 % ) , 7 % ( 6.5 to 7 % ) and 1.2 % ( 1 % to 1.5 % ) . Women had a higher prevalence than men when PAD was diagnosed with ABI only ; that is , asymptomatic PAD ( 12.6 % vs 9.4 % , P=.03 ) and severe limb ischemia ( 1.5 % vs 0.8 % , P<.008 ) . The prevalence of any PAD was 7.9 % in the age group 60 to 65 years and increased to 47.2 % among the age group 85 to 90 years . Severe limb ischemia occurred in 0.3 % in the youngest age group , was highest in the age group 80 to 84 years at 3.3 % , and declined to 2.5 % among the oldest . The prevalence of PAD differed between regions ( P<.0001 ) . CONCLUSIONS PAD is common in Sweden , and almost a fifth of all elderly individuals have some stage of this disease . Women are more often afflicted than men . The prevalence of severe ischemia , as a measure of critical limb ischemia , is about 1 % the population We tested whether cyclooxygenase 2 ( COX-2 ) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane ( TX ) bio synthesis in aspirin-treated essential thrombocythemia ( ET ) . Forty-one patients on chronic aspirin ( 100 mg/day ) and 24 healthy subjects were studied .  Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets ( r = 0.71 , P < .001 ) . The rate of TXA(2 ) bio synthesis in vivo , as reflected by urinary 11-dehydro-TXB(2 ) ( TXM ) excretion , and the maximal biosynthetic capacity of platelets , as reflected by serum TXB(2 ) , were higher in patients compared with aspirin-treated healthy volunteers . Serum TXB(2 ) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro . Patients were r and omized to adding the selective COX-2 inhibitor , etoricoxib , or continuing aspirin for 7 days . Etoricoxib significantly reduced by approximately 25 % TXM excretion and serum TXB(2 ) .  Fourteen of the 41 patients were studied again 21 ( + /- 7 ) months after the first visit . Serum TXB(2 ) was consistently reduced by approximately 30 % by adding NS398 in vitro , while it was completely suppressed with 50 microM aspirin . Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2 ) bio synthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1 . These findings may help in reassessing the optimal antiplatelet strategy in ET OBJECTIVES This study sought to determine the incidence of aspirin nonresponsiveness in addition to clopidogrel nonresponsiveness and whether this association identifies patients at an increased risk of drug-eluting stent ( DES ) thrombosis . BACKGROUND Nonresponsiveness to clopidogrel is a predictor of DES thrombosis . No prospect i ve data exist about the possible association of dual nonresponsiveness to clopidogrel and aspirin with DES thrombosis . METHODS Platelet function was assessed after a loading dose of 600 mg clopidogrel in 746 patients who had successful DES implantation followed by 6-month dual-antiplatelet therapy .  Platelet reactivity was assessed by light transmittance aggregometry using adenosine 5'-diphosphate , arachidonic acid , and collagen . The primary end point was definite/probable DES thrombosis at 6 months . The secondary end point was the composite of cardiac mortality and DES thrombosis . RESULTS The incidence of dual nonresponsiveness to aspirin and clopidogrel was 6 % . Definite/probable DES thrombosis was significantly higher in dual aspirin and clopidogrel nonresponders ( 11.1 % ) than in clopidogrel and aspirin responders ( 2.1 % , p < 0.001 ) , isolated clopidogrel nonresponders ( 2.2 % , p < 0.05 ) , or aspirin nonresponders ( 2.3 % , p < 0.05 ) . The incidence of the secondary end point was 4.4 % in isolated clopidogrel nonresponders , 2.3 % in isolated aspirin nonresponders , and 13.3 % in dual aspirin and clopidogrel nonresponders . Dual clopidogrel and aspirin nonresponsiveness was an independent predictor of DES thrombosis ( hazard ratio : 3.18 , 95 % confidence interval : 1.14 to 8.83 , p = 0.027 ) and the composite of cardiac mortality and DES thrombosis ( hazard ratio : 2.94 , 95 % confidence interval : 1.16 to 7.41 , p = 0.022 ) . CONCLUSIONS Dual nonresponsiveness to aspirin and clopidogrel is a relatively infrequent condition that identifies patients at a very high risk of DES thrombosis or death Prognostic markers help to stratify patients for treatment by identifying patients with different risks of outcome ( e.g. recurrence of disease ) , and are important tools in the management of cancer and many other diseases . Systematic review and meta-analytical approaches to identifying the most valuable prognostic markers are needed because ( sometimes conflicting ) evidence relating to markers is often published across a number of studies . To investigate the practicality of this approach , an empirical investigation of a systematic review of  tumour markers for neuroblastoma was performed ; 260 studies of prognostic markers were identified , which considered 130 different markers . The reporting of these studies was often inadequate , in terms of both statistical analysis and presentation , and there was considerable heterogeneity for many important clinical /statistical factors . These problems restricted both the extraction of data and the meta- analysis of results from the primary studies , limiting feasibility of the evidence -based approach . Guidelines for reporting the results of primary prognostic marker studies in cancer , and other diseases , are given in order to facilitate both the interpretation of individual studies and the undertaking of systematic review s , meta- analysis and , ultimately , evidence -based practice . General availability of full individual patient data is a necessary step forward and would overcome the majority of problems encountered , including poorly reported summary statistics and variability in cutoff level , outcome assessed and adjustment factors used . It would also limit the problem of reporting bias , although publication bias will remain a concern until studies are prospect ively registered . Such changes in practice would help important evidence -based review s to be conducted in order to establish the most appropriate prognostic markers for clinical use , which should ultimately improve patient care Reduced effectiveness of the most common antiplatelet drug , acetylsalicylic acid ( ASA , aspirin ) , in diabetes mellitus has been associated with a lowered platelet sensitivity to ASA and related to glycemic control in diabetic patients . Our objectives were ( a ) to monitor the chemical background of how chronic hyperglycemia affects platelet response to ASA in diabetes and ( b ) to study a chemical competition between the amount of bound acetyl residues and the extent of protein glycation in blood platelets . Using whole-blood impedance aggregometry and platelet function analyzer ( PFA-100 ) we observed a reduced platelet response to ASA in diabetic patients ( 14 % vs. 79 % for PFA-100 collagen-epinephrine occlusion time ) and an association between the index of glycemic control and platelet refractoriness to ASA ( rS=−0.378 ) . Impaired platelet response to ASA was related to enhanced platelet protein glycation ( 3.6±0.4 in diabetes vs. 2.3±0.4 µmol fructosamine/µg protein in control ) and reduced incorporation of acetyl residue into proteins of platelets from diabetic patients ( 47.4±2.0 in control vs. 33.1±0.7 µmol acetyl/µg protein in diabetic subjects ) . Incubation of blood platelets with increasing concentrations of glucose and ASA under in vitro conditions led to excessive modification in protein amino groups : glucose and ASA competed with each other in the course of nonenzymatic modifications , glycosylation , or acetylation , and their contributions to the occupancy of protein amino groups ( R2=0.22 for glucose , R2=0.43 for ASA ) were dependent upon the concentrations of glucose and ASA . Overall the effects of high glucose and high ASA on the overall occupancy of protein free amino groups are not additive . While at higher concentrations ASA overcomes the effects of hyperglycemia and retards glycation , high glucose makes acetylation less efficient , and therefore the result ant chemical modification becomes greatly reduced . In conclusion , diminished susceptibility of various platelet proteins and receptors on blood platelet membranes to acetylation and high ambient glucose might underlie the apparently differentiated sensitivity of blood platelets to ASA and determine platelet “ insensitivity to aspirin ” in diabetic Background and Purpose — Recent studies suggest that patients who do not respond to aspirin ( ASA ) therapy may be at increased risk of ischemic vascular events . The availability of simple to use point-of-care ( POC ) platelet function tests now potentially allows aspirin nonresponsiveness to be identified in routine clinical practice . However , there are very few data on whether the different tests produce consistent results . We therefore compared 2 POC tests ( PFA-100 device and the Ultegra-RPFA [ RPFA ] ) with conventional light transmission aggregometry ( LTA ) . Methods — Platelet function was assessed by all 3 tests in 100 patients receiving low-dose ASA therapy after transient ischemic attack ( TIA ) or ischemic stroke . Results — The incidence of ASA nonresponsiveness was 17 % by the RPFA and 22 % by the PFA-100 , compared with only 5 % by LTA ( ie , as defined with both arachidonic acid and ADP ) . Agreement between the RPFA and the PFA-100 and arachidonic acid induced LTA was poor ( & kgr;=0.16 , 95 % CI , −0.08 to 0.39 , P=0.11 ; and & kgr;=0.09 −0.12 to 0.30 , P=0.32 , respectively ) . Agreement between the 2 POC tests was also poor ( & kgr;=0.14 , −0.08 to 0.36 , P=0.15 ) . Only 2 % of patients were aspirin nonresponders by all 3 tests . Conclusions — The prevalence of apparent ASA nonresponsiveness was higher with both the POC tests than with LTA . However , agreement between the tests was poor and very few patients were ASA nonresponsive by all 3 tests . Aspirin nonresponsiveness is therefore highly test-specific and large prospect i ve studies will be required to determine the prognostic value of each of the separate tests 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 . ) INTRODUCTION An increasing amount of evidence indicates that platelet reactivity , despite a st and ard anti-thrombotic therapy , is a potential risk factor for recurrent myocardial ischemia in patients with coronary artery disease . We now hypothesize that this condition , measured by collagen-epinephrine ( CEPI ) or collagen-ADP ( CADP ) closure times ( CT ) by Platelet Function Analyzer ( PFA-100 ) , may predict the recurrence of coronary events after percutaneous coronary intervention ( PCI ) . MATERIAL S AND METHODS CEPI and CADP-CT  were measured 30+/-8 h after PCI in 175 consecutive patients admitted with a diagnosis of stable angina ( n=94 ) or acute coronary syndromes ( n=81 ) and prospect ively followed up for a mean period of 6 months . We stratified the patients in accordance to both the CEPI-CT ( 190 s ) , reflecting the intensity of cycloxygenase inhibition by aspirin and the distribution into quartiles for CADP-CT . RESULTS CEPI-CT<190 s as well as CADP-CT<82 s were associated with a higher rate of clinical recurrence ( hazard ratio 8.5 , p<0.001 and 22.9 , p<0.001 , respectively ) . Multivariate analysis after adjustment for other risk factors confirmed that the lowest CADP-CT quartile significantly correlates with the risk of recurrent coronary events ( hazard ratio 36.5 , p<0.01 ) , as well as CEPI-CT<190 s ( hazard ratio 6.7 , p=0.01 ) . CONCLUSIONS An enhanced platelet function after PCI when measured under high shear rates by PFA-100 is an independent predictor of a worst clinical outcome , even during a short term follow-up and may help in patients risk stratification Non-responsiveness to aspirin as detected by laboratory tests may identify patients at high risk for future vascular events . The aim of this prospect i ve study was to evaluate whether non-responsiveness to aspirin  is stable over time . Ninety-eight patients with stable peripheral arterial occlusive disease ( PAOD ) treated with 100 mg/d aspirin were followed over a median timeframe of 17 months . Platelet function tests were performed initially and at follow-up using arachidonic acid-induced light transmittance aggregometry ( LTA ) in native platelet-rich plasma with the Behring Coagulation Timer ® and by measuring the collagen−epinephrine closure time ( CT ) on a Platelet Function Analyzer ( PFA-100 ® ) . When determining platelet function using LTA , four patients ( 4.1 % ) had residual platelet function ( i.e. , MaxAggr ≥78 % ) despite aspirin treatment , whereas , according to the PFA-100 ® results , 12 patients ( 12.2 % ) were identified as non-responders ( i.e. , CT < 192 s ) . Fifty-seven patients who were still under treatment with 100 mg/d aspirin at the time of follow-up provided a second blood sample . Further platelet function tests with the PFA-100 ® system identified a persistent non-responsiveness to aspirin over time in three patients ( 5.3 % ) whereas four ( 7.0 % ) and 15 ( 26.3 % ) patients had changes in response status when platelet function was assessed by LTA and on the PFA-100 ® , respectively . We conclude that true non-responsiveness to aspirin  is a rare phenomenon in stable PAOD patients . Furthermore , we conclude that in a number of patients , aspirin non-responsiveness is not stable over time The efficacy of low-dose aspirin in type 2 diabetes mellitus ( T2DM ) has been question ed . We tested if twice daily dosing of aspirin would be more effective in T2DM , possibly due to increased platelet turnover . A r and omised cross-over study compared 75 mg aspirin OD , 75 mg BID and 320 mg OD ( ≥ 2 week treatment periods ) in 25 patients with T2DM and micro- or macrovascular complications . Platelet responses were examined by impedance aggregometry ( WBA ) and the IMPACT-R aspirin  test in whole blood , light transmittance aggregometry in platelet-rich plasma ( LTA ) , and urinary 11-dehydro-thromboxane B2 ( TxM ) . Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD ( 9.7 ± 4.5 vs. 12.6 ± 3.5 ohm ; p = 0.003 ) or to 320 mg OD ( 11.5 ± 4.2 Ohms ; p = 0.049 ) . WBA responses to collagen were similarly attenuated by BID or high dosing ( by 12 - 14 % ; p = 0.02 for both ) . The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD ( p = 0.049 ) , but not to 320 mg OD . AA-induced aggregation by LTA was < 6.5 % on all occasions , with no differences between aspirin dosages . TxM was reduced after 320 mg OD ( p = 0.002 ) , but not 75 mg BID ( p = 0.07 ) . Reticulated platelets were highly correlated with mean platelet volume ( MPV ; r2 = 0.74 , p<0.0001 ) . Both markers for platelet turnover were correlated with AA-induced WBA , but neither identified patients who benefited from BID dosing dependably . In conclusion , twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients . Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest Background Creatinine kinase-MB ( CK-MB ) and cardiac troponin I ( cTnI ) elevations are highly specific for myonecrosis after percutaneous coronary intervention ( PCI ) . Aspirin is used to prevent thrombotic complications . Several studies have shown that some individuals exhibit a reduced or completely missing antiplatelet response to aspirin . The aim of this study is to investigate the effects of platelet reactivity despite aspirin therapy on CK-MB and cTnI levels after elective percutaneous coronary interventions despite 600 mg loading dose of clopidogrel . Methods One hundred fourteen ( mean age 61.2 ± 9.3 years , 78.1 % male ) patients receiving 300 mg daily enteric coated aspirin for at least 7 days with documented coronary artery disease were included in the study . Platelet reactivity  despite aspirin was measured by platelet function analyzer (PFA)-100 collagen/epinephrine cartridge . Blood sample s for CK-MB and cTnI were obtained before and at 6 , 24 , and 36 h after the PCI . Persistent platelet reactivity was defined when collagen/epinephrine closure time < 165 s. Results A total of 87 ( 76.4 % ) patients were noted to have normal platelet reactivity ( Group A ) , and 27 ( 23.6 % ) had persistent platelet reactivity ( Group B ) . The elevations of CK-MB and cTnI levels were statistically significant within the groups ( both P < 0.001 ) . However , there were no significant differences in the CK-MB and cTnI levels of the groups at baseline and after PCI for all studied hours . Conclusion Persistent platelet reactivity was not associated with increased risk of CK-MB , cTnI elevations in low-to-intermediate risk PCI patients BACKGROUND Aspirin is one of the main therapeutics in prevention of cardiovascular events due to its antiplatelet activity . However , a sufficient inhibition of platelet function by aspirin is not always achieved . This means that the extent of protection from cardiovascular event is limited . Recently , several studies have introduced the concept of residual platelet reactivity during aspirin therapy and suggested that about 40 % of aspirin users may not respond adequately . We sought to determine whether the profile and prevalence of residual platelet reactivity , measured with the platelet function analyzer ( PFA-100 ; Dade/Behring , Marburg , Germany ) device could predict a recurrent cardiovascular event in patients undergoing coronary artery bypass surgery . METHODS A cohort of 202 consecutive patients receiving primary coronary artery bypass surgery during 2004 was prospect ively recruited . All patients postoperatively received regular st and ard daily 100 mg aspirin .  Platelet function was analyzed by the PFA-100 at 30 + /- 6 days after surgery . A PFA100 closure time less than 190 seconds was defined as residual platelet reactivity . Eighty-six patients ( 43 % ) showed residual platelet reactivity . The mean follow-up time was 32 + /- 10 months and was 100 % complete . RESULTS A total of 75 cardiovascular events have been registered . The majority of these events were among patients with residual platelet activity ( p = 0.001 ) . Out of this number , graft failure was documented in 25 patients . The 42-month freedom from major cardiovascular events was significantly better for patients with adequate platelet inhibition ( p = 0.001 ) . At multivariable analysis residual platelet reactivity ( p = 0.012 ) , incomplete revascularization ( p = 0.029 ) , and diabetes ( p = 0.0009 ) were independently associated with occurrence of negative events . CONCLUSIONS Our results demonstrate that high residual platelet reactivity independently correlates with a worst clinical outcome in patients treated by  coronary artery bypass surgery . The PFA-100 point care test could cheaply and simply discover this condition and contribute to improve the outcome of this subset of patients This study determined if meloxicam , a selective cyclooxygenase (COX)-2 inhibitor , interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane ( Tx ) B(2 ) endpoints in healthy volunteers . Eight male and 8 female volunteers participated in this open-label , r and omized , two-treatment , two-way crossover trial . Treatment 1 was meloxicam ( 15 mg qd ) over 4 days , and then aspirin ( 100 mg qd ) was ingested 2 hours after meloxicam for an additional 7 days . Blood sample s were taken 2 , 6 , and 24 hours after the last dose . Treatment 2 consisted of only aspirin ( 100 mg ) over 2 days . Sample s were taken at the same time points . Each subject received both treatments with a 2-week washout between the treatment periods . Treatments were safe and well tolerated . The initial 4-day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB(2 ) by 64 % + /- 19 % . Addition of aspirin ( 100 mg qd ) for 7 days result ed in complete inhibition of aggregation and TxB(2 ) for 24 hours . Two-day treatment with only 100 mg aspirin also result ed in complete inhibition of platelet aggregation and TxB(2 ) . These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX-1 in platelets , thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB(2 ) levels , and that meloxicam is selective for COX-2 BACKGROUND Interindividual variability in response to aspirin has been popularized as ' resistance ' . We hypothesized that faster recovery of platelet cyclooxygenase-1 activity may explain incomplete thromboxane ( TX ) inhibition during the 24-h dosing interval . OBJECTIVE To characterize the kinetics and determinants of platelet cyclooxygenase-1 recovery in aspirin-treated diabetic and non-diabetic patients . PATIENTS / METHODS One hundred type 2 diabetic and 73 non-diabetic patients on chronic aspirin 100 mg daily were studied .  Serum TXB(2 ) was measured every 3 h , between 12 and 24 h after a witnessed aspirin intake , to characterize the kinetics of platelet cyclooxygenase-1 recovery . Patients with the fastest TXB(2 ) recovery were r and omized to aspirin 100 mg once daily , 200 mg once daily or 100 mg twice daily , for 28 days and TXB(2 ) recovery was reassessed . RESULTS AND CONCLUSIONS Platelet TXB(2 ) production was profoundly suppressed at 12 h in both groups . Serum TXB(2 ) recovered linearly , with a large interindividual variability in slope . Diabetic patients in the third tertile of recovery slopes ( ≥ 0.10 ng mL(-1 ) h(-1 ) ) showed significantly higher mean platelet volume and body mass index , and younger age . Higher body weight was the only independent predictor of a faster recovery in non-diabetics . Aspirin 100 mg twice daily completely reversed the abnormal TXB(2 ) recovery in both groups . Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low-dose aspirin in patients with and without diabetes . Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen OBJECTIVES The purpose of this study was to evaluate the effects of aspirin and clopidogrel response on  myonecrosis after percutaneous coronary intervention ( PCI ) with glycoprotein ( GP ) IIb/IIIa blockade . BACKGROUND Aspirin and clopidogrel resistance is increasingly recognized , but its effects on PCI outcomes with GP IIb/IIIa blockade are unknown . METHODS This was a prospect i ve , pre-specified sub study of the BRIEF-PCI ( Brief Infusion of Intravenous Eptifibatide Following Successful Percutaneous Coronary Intervention ) trial , which r and omized 624 patients to 18-h or < 2-h eptifibatide infusion after uncomplicated PCI . To be eligible , patients must have been pre-treated with aspirin ( > or=5 days ) and clopidogrel ( 75 mg/day > or=5 days , 300 mg loading > or=6 h , or 600 mg loading > or=2 h ) and must not have received GP IIb/IIIa inhibitors within 48 h. Verify-Now Aspirin and Clopidogrel ( P2Y(12 ) ) assays were performed at baseline before PCI . Patients with aspirin reaction unit ( ARU ) > or=550 were labeled as aspirin resistant . Clopidogrel low-responders were defined as those in the lowest quartile of platelet inhibition . The primary end point was the prevalence of myonecrosis within 24 h after PCI . RESULTS We enrolled 209 patients into our sub study , of which 185 had aspirin response assessed , 198 had clopidogrel response assessed , and 174 had both assessed . There were 4.9 % who were aspirin resistant . Clopidogrel low-responders were defined as those in the lowest quartile with platelet inhibition < 19 % . Only 1.1 % had both aspirin resistance and low clopidogrel response . There was no difference in myonecrosis prevalence among aspirin-resistant compared with aspirin-sensitive patients ( 11.1 % vs. 27.8 % , p = 0.259 ) or among clopidogrel low-responders compared with clopidogrel responders ( 23.5 % vs. 29.3 % , p = 0.433 ) . CONCLUSIONS Aspirin and clopidogrel response did not affect myonecrosis prevalence amongst patients who received eptifibatide for PCI BACKGROUND Aspirin resistance appears to be an important prognostic factor in patients with coronary artery disease , yet there is no st and ardized method to measure it and limited data on its correlation to clinical outcomes . METHODS In a prospect i ve study we followed 103 patients ( mean age 64 years ) with acute coronary syndrome ( ACS ) without ST segment elevation who were treated with 100 mg of aspirin ( ASA ) daily . Optical platelet aggregometry using cationic propyl gallate ( CPG ) as an inductor was measured at ACS onset and after 3 , 12 , 24 , 36 , and 48 months . ASA responsiveness was defined both by the slope of the aggregation curve ( < 53%/min ) and by spontaneous aggregation ( < 5 % ) . The primary outcomes were the recurrence of ACS or stroke . RESULTS Patients with ACS exhibited a greater prevalence of  ASA resistance ( 55 % ) than healthy volunteers ( 4 % ; p<0.01 ) . ASA resistance occurred more often in patients with type 2 diabetes , hypertriacylglycerolemia , and decreased HDL levels , and in smokers ( p<0.05 ) . A single assessment of platelet aggregometry was sufficient to identify ASA-resistant patients . During the 4-year follow-up , the patients with ASA resistance had an 88 % incidence of recurrent cardiovascular events versus 46 % for the patients without ASA resistance ( p<0.01 ) . In the subgroup with recurrent cardiovascular ( CV ) events , significantly more patients were ASA-resistant than in the subgroup without recurrent CV events ( 72 % vs. 8 % , p<0.01 ) . CONCLUSION ASA resistance measured by CPG-induced platelet aggregometry is more common among patients with ACS and some metabolic risk factors , and ASA-resistant patients have a significantly higher recurrence of cardiovascular events We performed a prospect i ve cohort trial on 220 patients undergoing elective off-pump coronary artery bypass surgery and taking  aspirin to evaluate the effect of aspirin resistance on myocardial injury . The patients were divided into aspirin responders and aspirin non-responders by the value of the aspirin reaction units obtained preoperatively using the VerifyNow ™ Aspirin Assay . The serum levels of troponin I were measured before surgery and 1 , 6 , 24 , 48 and 72 hr after surgery . In-hospital major adverse cardiac and cerebrovascular events , graft occlusion , the postoperative blood loss and reexploration for bleeding were recorded . Of the 220 patients , 181 aspirin responders ( 82.3 % ) and 39 aspirin non-responders ( 17.7 % ) were defined . There were no significant differences in troponin I levels ( ng/mL ) between aspirin responders and aspirin non-responders : preoperative ( 0.04 ± 0.08 vs 0.03 ± 0.06 ; P = 0.56 ) , postoperative 1 hr ( 0.72 ± 0.87 vs 0.86 ± 1.10 ; P = 0.54 ) , 6 hr ( 2.92 ± 8.76 vs 1.50 ± 2.40 ; P = 0.94 ) , 24 hr ( 4.16 ± 13.44 vs 1.25 ± 1.95 ; P = 0.52 ) , 48 hr ( 2.15 ± 7.06 vs 0.65 ± 0.95 ; P = 0.64 ) and 72 hr ( 1.20 ± 4.63 vs 0.38 ± 0.56 ; P = 0.47 ) . Moreover , no significant differences were observed with regard to in-hospital outcomes . In conclusion , preoperative aspirin resistance does not increase myocardial injury in patients undergoing off-pump coronary artery bypass surgery . Postoperative dual antiplatelet therapy might have protected aspirin resistant patients Background —Postoperative thromboembolic stroke affects 2 % to 3 % of patients undergoing carotid endarterectomy ( CEA ) and is preceded by 1 to 2 hours of increasing cerebral embolization . Previous work has demonstrated that high rates of postoperative embolization are associated with increased platelet reactivity to adenosine 5′-diphosphate ( ADP ) . Our hypothesis was that preoperative administration of the platelet ADP antagonist clopidogrel could reduce postoperative embolization . Methods and Results —One hundred CEA patients on routine aspirin therapy ( 150 mg ) were r and omized to 75 mg clopidogrel ( n=46 ) or placebo ( n=54 ) the night before surgery . Platelet response to ADP was assessed by whole-blood flow cytometry . The number of emboli detected by transcranial Doppler within 3 hours of CEA was independently quantified . Time taken from flow restoration to skin closure was used as an indirect measure of the time to secure hemostasis . In comparison with placebo , clopidogrel produced a small ( 8.8 % ) but significant reduction in the platelet response to ADP ( P < 0.05 ) while conferring a 10-fold reduction in the relative risk of those patients having > 20 emboli in the postoperative period ( odds ratio , 10.23 ; 95 % CI , 1.3 to 83.3 ; P = 0.01 , Fisher ’s exact test ) . However , in the clopidogrel-treated patients , the time from flow restoration to skin closure ( an indirect marker of hemostasis ) was significantly increased ( P = 0.04 , Fisher ’s exact test ) , although there was no increase in bleeding complications or blood transfusions . Conclusions —This is the first study to show that a CEA patient ’s postoperative thromboembolic potential can be significantly reduced by targeted preoperative antiplatelet therapy without increasing the risk of bleeding complications Background The benefits of aspirin as an anti-platelet agent are well established ; however , there has been much debate about the lack of uniformity in the efficacy of aspirin to inhibit platelet function . In some patients , aspirin fails to inhibit platelets even where compliance has been verified , a phenomenon which has been termed “ aspirin resistance ” . These patients may in turn be at a higher risk of future vascular events . The proportion of “ resistant ” patients identified depends on the type of platelet function test . Therefore , the aim of this systematic review is to determine which , if any , platelet function test has utility in terms of identifying patients with a high risk of vascular events . The review has been registered with PROSPERO ( CRD42012002151 ) . Methods Relevant studies will be sought from bibliographic data bases . Trials registers will be search ed for ongoing studies . Reference lists will be checked and subject experts contacted . There will be no date or language restrictions . St and ard review ing methodology to minimise bias will be employed . Any prospect i ve studies in patients on aspirin therapy and assessing platelet function in relation to relevant clinical outcomes will be included , as will studies reporting prognostic models . Risk of bias assessment will be based on the Quality Assessment of Diagnostic Accuracy Studies guidelines , and suitable criteria for assessing quality of prognostic studies . Data on test accuracy measures , relative risks , odds or hazard ratios will be extracted and meta-analysed , where possible , using a r and om-effects model to account for between- study heterogeneity . Where appropriate , the causes of heterogeneity will be explored through meta-regression and sub-group or sensitivity analyses . If platelet function testing is demonstrated to have diagnostic/predictive utility in a specific population , the potential for a cost-effectiveness analysis will be considered and , if possible , an economic model constructed . This will be supported by a systematic review of existing economic evaluation studies . Discussion The results of the review could indicate if platelet function test(s ) could lead to a reliable prediction of the risk of clinical ly important events in a defined population , and thus support investigations into adjustments to therapy in order to compensate for a predicted poor response to st and ard aspirin 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 Platelet hyperfunction contributes to acute coronary syndromes ( ACS ) . Thus , we hypothesized that platelet function under high shear stress predicts recurrent ACS during long-term follow-up of ACS patients . PATIENTS AND METHODS Consecutive ACS patients ( n = 208 ) were prospect ively followed-up for an average of 28 months . Platelet function was measured with the platelet function analyzer ( PFA-100 ; Dade Behring , Marburg , Germany ) at baseline for collagen/adenosine diphosphate closure times ( CADP-CT ) and for collagen/epinephrine closure times ( CEPI-CT ) after infusion of a uniform dose of 250 mg aspirin . RESULTS Of the conventional risk factors , only the prevalence of diabetes was higher in ACS patients with re-events . However , use of clopidogrel and use of beta blockers were also slightly lower in patients with re-events ( P < 0.05 ) . The unadjusted risk hazard ratio ( HR ) for re-events was 3.3 [ 95 % confidence interval ( 95 % CI ) : 1.4 - 7.4 ; P = 0.005 ] in those patients with the shortest CADP-CT values ( lowest quartile ) . Similarly , the risk was 2.0-fold higher ( 95 % CI : 1.1 - 3.6 ; P = 0.02 ) in ACS patients with CEPI-CT < 300 s as compared with CEPI-CT > or = 300 s. Inclusion of diabetes , clopidogrel and beta blockers in a multivariate Cox regression model enhanced the predictive value of CEPI-CT ( HR : 2.7 ) . Inclusion of von Willebr and factor levels did not alter the HR for recurrent ACS ( HR : 2.1 ; 95 % CI : 1.1 - 5.2 ; P = 0.03 ) for CEPI-CT < 300 s , but reduced the HR for CADP-CT ( HR : 2.8 , 95 % CI : 0.8 - 9.8 ; P = 0.11 ) . CONCLUSION Shortened CT values reflect biologically relevant platelet hyperfunction in patients with ACS because they predict recurrent ACS There is some data available on the role of high on-treatment platelet reactivity by ADP whereas , as regards arachidonic acid or other agonists , there is no proof of the best cut-off for identifying population s with a different cardiovascular outcome by the construction of appropriate receiver-operator characteristics ( ROC ) curves . We enrolled 1,108 acute coronary syndrome patients undergoing percutaneous coronary intervention ( PCI ) with stent implantation  and followed them up for 12 months . Platelet reactivity was assessed by light transmission aggregometry ( LTA ) using 10 microM ADP , 1 mM arachidonic acid ( AA ) and 2 microg/ml collagen . At a 12-month follow-up , we found 37 cardiovascular deaths ( 3.3 % ) , 54 non-fatal myocardial infa rct ions ( MI ) ( 4.8 % ) and 154 target vessel revascularisations ( TVR ) ( 13.8 % ) . ROC analysis demonstrated that 10 microM ADP LTA , 1 mM AA and 2 microg/ml collagen LTA were able to distinguish between patients with and without subsequent cardiovascular death and non-fatal MI ( area under the curve for 10 microM ADP 0.63 ( 0.55 - 0.71 ) , p<0.001 ; for 1 mM AA 0.68 ( 0.61 - 0.76 ) , p<0.0001 ; for 2 microg/ml collagen 0.62 ( 0.52 - 0.73 ) , p<0.0111 ) , whereas no association was demonstrated with the occurrence of TVR . Ten microM ADP LTA > or=55 % , 1 mM AA LTA > or=15 % and 2 microg/ml collagen LTA > or=31 % were identified as the optimal cut-off to predict cardiovascular death and non-fatal MI at 12-month follow-up . The contemporary platelet hyperreactivity to more than one agonist was associated with a higher risk of 12-month cardiovascular death and MI , whereas isolated platelet hyperreactivity to only one agonist had not a predictive value [ 10 microM ADP LTA > or=55 % + 1 mM AA LTA > or=15 % : odds ratio [OR]=3.6(2.4 - 6.1 ) , p<0.0001 ; ADP LTA > or=55 % + 1 mM AA LTA > or=15 % + 2 microg/ml collagen LTA > or=31 % : OR=4.7(2.9 - 7.7 ) , p<0.0001 ] . In this prospect i ve study on a large number of acute coronary syndrome patients undergoing stent implantation  , we have found that high on-treatment platelet reactivity measured by LTA induced by more than one agonist -- AA , ADP , collagen -- is an independent risk factor for 12-month cardiovascular death and non-fatal MI . Isolated platelet hyperreactivity to only one agonist has not a predictive value for clinical recurrences BACKGROUND Several studies suggest that acetylsalicylic acid ( ASA ) is less effective in preventing thrombotic events in ASA nonresponder patients . If so , the thrombotic event rate in ASA nonresponders should be higher than in ASA responders . OBJECTIVE To conduct a prospect i ve , multicentre observational pilot study to determine the thrombotic event rates in ASA responders and nonresponders . PATIENTS AND METHODS Patients undergoing nonurgent coronary artery bypass grafting ( CABG ) who were prescribed 325 mg ASA/day were recruited . Patients were classified as an ASA responder or nonresponder based on the ASA effect ( or lack thereof ) on their bleeding times . All thrombotic events that occurred in the two years following CABG were recorded . These data were stored in a blinded fashion until the last patient follow-up , and then adjudicated by a validation committee . RESULTS A total of 289 patients recruited at three sites completed the two-year follow-up . Of these patients , 45.3 % were classified as ASA responders and 54.7 % were classified as ASA nonresponders . Of ASA responders , 6.9 % had thrombotic events compared with 9.5 % of the ASA nonresponders , but this difference was not significant ( P=0.526 ) . CONCLUSIONS While ASA responder or nonresponder status did not appear to affect the thrombotic event rate in patients undergoing nonurgent CABG , the possibility that ASA responder or nonresponder status affects the thrombotic event rate in more acutely ill CABG patients can not be excluded Background – We investigated the platelet function in stroke patients treated with aspirin [ acetylsalicylic acid ( ASA ) ] for secondary stroke prevention during a follow‐up period of 1 year INTRODUCTION The purpose of the present study was to study the concept of aspirin resistance or non-responsiveness by investigating the response to long-term aspirin therapy in patients with a former acute myocardial infa rct ion ( AMI ) . MATERIAL S AND METHODS Patients with an AMI ( n=202 ) r and omly assigned to aspirin 160 mg/day ( n=71 ) , aspirin 75 mg/day and warfarin ( INR 2.0 - 2.5 ) ( n=58 ) or warfarin ( INR 2.8  - 4.2 ) ( n=73 ) were evaluated by the PFA-100(R ) , biochemical variables and clinical events after a mean treatment period of 4 years . RESULTS The limit for being an aspirin non-responder was defined as the 95th percentile value in the warfarin alone group ( 196 s ) with the epinephrine cartridge . In patients on aspirin alone 25/71 ( 35 % ) were non-responders and on the combination 23/58 ( 40 % ) . With the adenosine diphosphate ( ADP ) cartridge only minor differences were found . The levels of thromboxane B(2 ) in both aspirin groups , in responders as well as in non-responders , were extremely low compared to the warfarin alone group . Evaluating both aspirin groups together ( n=129 ) , the levels of soluble P-selectin were significantly higher in non-responders as compared to responders ( p=0.012 ) . During the observation period of 4 years with limited number of events , there was a tendency for higher event rates in non-responders as compared to responders ( 36 % vs. 24 % , p=0.28 ) . CONCLUSIONS In our evaluation of the PFA-100(R ) a considerable number of post-AMI patients seemed to be non-responders to long-term aspirin therapy in doses of 75 and 160 mg/day . Circulating levels of P-selectin were higher in the non-responders . A tendency to higher incidence of clinical events among non-responders was observed In medical research , continuous variables are often converted into categorical variables by grouping values into two or more categories . We consider in detail issues pertaining to creating just two groups , a common approach in clinical research . We argue that the simplicity achieved is gained at a cost ; dichotomization may create rather than avoid problems , notably a considerable loss of power and residual confounding . In addition , the use of a data -derived ' optimal ' cutpoint leads to serious bias . We illustrate the impact of dichotomization of continuous predictor variables using as a detailed case study a r and omized trial in primary biliary cirrhosis . Dichotomization of continuous data is unnecessary for statistical analysis and in particular should not be applied to explanatory variables in regression models Aspirin resistance may increase the risk of major adverse cardiac events ( MACE ) more than threefold in patients with stable coronary artery disease ( CAD ) . This study aim ed to determine the prevalence of aspirin resistance in patients with stable CAD , the role of aspirin resistance on outcome in the follow-up , and the effect of clopidogrel therapy in MACE prevention in aspirin-resistant individuals . We detected the prevalence of aspirin resistance in 234 patients with stable CAD . Platelet function was determined by PFA-100 with collagen and /or epinephrine and collagen and /or ADP cartridges . The mean follow-up time was 20.6 ± 6.9 months . The primary endpoints of the study were occurrence of myocardial infa rct ion , unstable angina , stroke and cardiac death . Of patients , 22.2 % ( n = 52 ) were aspirin resistant by PFA-100 . During follow-up , MACE occurred in eight patients ( 15.4 % ) with aspirin resistance and in 20 patients ( 11.0 % ) with aspirin-sensitive platelet aggregation ( P = 0.269 ) . MACE increased in aspirin-resistant patients after termination of clopidogrel therapy . Eleven patients experienced MACE after cessation of clopidogrel therapy ( P < 0.001 ) . The MACE risk in patients with stable CAD having detected aspirin resistance was similar compared with patients having aspirin-sensitive platelet aggregation by PFA-100 . The MACE prevalence increased during follow-up , however , just after cessation of clopidogrel therapy AIMS We assessed prospect ively the association between occurrence of post-discharge non-CABG-related TIMI major and minor bleeding  and post-treatment platelet reactivity in patients with non-ST elevation acute coronary syndrome ( NSTE ACS ) . METHODS AND RESULTS Five hundred and ninety-seven consecutive patients admitted with NSTE ACS were prospect ively included . Between hospital discharge and one month follow-up , we observed 16 ( 2.7 % ) non-CABG-related TIMI haemorrhagic complications including five ( 0.84 % ) major and 11 ( 1.8 % ) minor bleeds . Patients with bleeding had significantly lower post-treatment values of ADP-induced aggregation ( 43+/-14 % versus . 56+/-19 % , p=0.002 ) and platelet reactivity index VASP ( 43+/-14 % versus 54+/-23 % ; p=0.04 ) and a trend for lower values of arachidonic acid-induced aggregation ( 2.4+/-5.4 versus 13+/-21 ; p=0.27 ) . After stratification by quartiles based on post-treatment ADP-induced platelet aggregation , we identified patients in the first quartile as hyper-responders with very low post-treatment platelet reactivity , below < 40 % . The risk of TIMI major and minor bleeding was significantly higher in the first quartile of hyper-responders than in the others quartiles : 10 ( 6.6 % ) versus six ( 1.4 % ) , p=0.001 . CONCLUSIONS Our results suggest that assessment of post-treatment platelet reactivity might be used to detect hyper-responders to antiplatelet therapy with higher risk of non-CABG related bleeding and tailor antiplatelet therapy according to both ischaemic and bleeding risk OBJECTIVE To study the prevalence and importance of aspirin resistance in patients with an evolving acute myocardial infa rct ion ( AMI ) by use of the Platelet Function Analyzer-100 . INTRODUCTION Previous studies have demonstrated the existence of aspirin resistance , but the clinical relevance of the phenomenon remains to be clarified . If aspirin resistant patients comprise a high-risk subgroup , it might be expected that the prevalence of aspirin resistance in patients with AMI would be higher than in patients without AMI . We hypothesized that the prevalence of aspirin resistance in patients with AMI was twice the prevalence in patients without AMI . METHODS We included 298 consecutive patients with known cardiovascular disease who were admitted to hospital with symptoms suggestive of an AMI . All had been taking aspirin 150 mg/day for at least 7 days prior to hospital admission .  Platelet function was measured immediately at admission , and aspirin resistance was defined as a collagen/epinephrine Closure Time ( CT(CEPI))<165 s. RESULTS We found that 70 ( 23.5 % ) patients were  aspirin resistant , and 70 ( 23.5 % ) patients ended up with the diagnosis of an AMI . The prevalence of aspirin resistance was significantly higher in patients with AMI as compared to patients without ( 36 % versus 20 % , OR 2.26 , CI 95 % 1.19 - 4.22 , p=0.0058 ) . The CT(CEPI ) measured at admission was an independent factor associated with an AMI . CONCLUSIONS  Aspirin resistance is present in almost one fourth of patients admitted to hospital with symptoms suggestive of an AMI , and aspirin resistance is significantly associated with the diagnosis of a definite AMI OBJECTIVES We have prospect ively investigated the association between aspirin and clopidogrel responses and the clinical predictors of non response . METHODS 635 Non ST Elevation Acute Coronary Syndrome ( NSTE ACS ) patients were included and received loading doses of 250 mg aspirin and 600 mg clopidogrel . We analyzed post-treatment maximal intensity of arachidonic acid and ADP-induced platelet aggregation ( AA-Ag and ADP-Ag ) and Platelet Reactivity Index of VAsodilator-Stimulated Phosphoprotein ( PRI VASP ) . Aspirin and clopidogrel non responses were defined respectively by AA-Ag>30 % and ADP-Ag>70 % . RESULTS Aspirin non responders patients had significantly higher ADP-Ag and PRI VASP than aspirin responders : 63.7+/-15.9 % vs 55+/-19 % ( p=0.0001 ) and 73.6+/-13.3 % vs 53+/-23 % ( p=0.0001 ) respectively and the rate of clopidogrel non responders was higher among aspirin non responders than aspirin responders : 36.7 % vs 22.7 % ( p=0.003 ) . In addition , clopidogrel non responders had significantly higher AA-Ag and rate of aspirin non responders than clopidogrel responders : 21.6+/-24 % vs 10.3+/-19 % ( p=0.0001 ) and 22.8 % vs 12.9 % ( p=0.003 ) respectively . Age and Body Mass Index ( BMI ) were significantly associated with non response to Clopidogrel ( p=0.035 and 0.02 respectively ) and diabetes mellitus by trend ( p=0.07 ) . CONCLUSION We observed a relationship between aspirin and clopidogrel non responses and an association between age , BMI and diabetes mellitus and clopidogrel response BACKGROUND Hemostatic drugs are widely thought to be unnecessary and potentially detrimental in off-pump coronary artery bypass graft surgery ( OPCABG ) , despite well-established use in on-pump surgery . In a r and omized , prospect i ve OPCABG trial , we assessed efficacy and safety of aprotinin through a comprehensive assessment of graft patency and hematologic function . METHODS Sixty patients were r and omly assigned to full-dose aprotinin or placebo . Heparin was titrated to a kaolin-based activated clotting time of greater than 300 seconds . Exclusionary criteria included creatinine greater than 2 mg/dL , conversion to on-pump CABG , and preoperative GPIIb/IIIa inhibition .  Hematologic assessment s were obtained preoperatively , at the end of surgery , and on days 1 and 3 : mean platelet volume , thrombin generation ( prothrombin fragment 1.2 assay ) , and aspirin resistance using a modified thrombelastography , whole blood aggregometry , 11-dehydro-thromboxane B2 levels , and flow cytometry . Thrombotic events were defined as postoperative myocardial infa rct ion by electrocardiography or elevated troponin I , clinical stroke by examination and head computed tomography , and bypass graft failure by multichannel computed tomography angiography on day 5 . RESULTS Aprotinin was associated with a significant reduction in intraoperative and postoperative blood loss compared with placebo but had no effect on transfusion rates . Patients treated with aprotinin had significantly fewer thrombotic events ( 3 % versus 23 % , p < 0.05 , Fisher 's exact test ) and less postoperative aspirin resistance ( 20 % versus 46 % , respectively , p < 0.05 , Fisher 's exact test ) . Postoperative prothrombin fragment 1.2 level was reduced by aprotinin use . CONCLUSIONS Aprotinin reduced perioperative bleeding after OPCABG . Preserved aspirin sensitivity in the aprotinin group may explain the observed reduction in thrombotic events and might be related to the suppression of perioperative and transmyocardial thrombin formation 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 Objective : To evaluate residual platelet activity in a consecutive cohort of patients treated with dual antiplatelet therapy after coronary stent implantation  Design : Prospect i ve single-centre cohort study . Setting : University hospital in Germany . Patients : 480 patients with symptomatic coronary artery disease ( n = 221 ( 46 % ) or acute coronary syndrome ( ACS ; n = 259 ( 54 % ) stable angina ) were studied . Platelet activity was measured by collagen- ( 5 µg/ml ) and adenosine diphosphate- ( ADP ; 20 µmol/l ) induced platelet aggregation to assess post-treatment activity in patients treated with acetylsalicylic acid ( 500 mg bolus intravenously followed by 100 mg once a day ) and clopidogrel ( 600 mg loading dose followed by 75 mg once a day ) Main outcome measures : Increased residual platelet activity ( IRPA ) was defined if platelet aggregation was in the upper tertile of values in the patient collective . Association of epidemiological factors with IRPA was evaluated in a multivariate logistic regression analysis . Results : IRPA-ADP was found in 53 patients ( 11.0 % ) and IRPA-collagen in 42 patients ( 8.8 % ) . ACS was associated with IRPA independently from other factors ( for IRPA-collagen : odds ratio ( OR ) = 2.3 , 95 % confidence interval ( CI ) 1.2 to 4.5 , p<0.05 ; for IRPA-ADP : OR = 2.4 ; 95 % CI 1.3 to 4.4 , p<0.01 ; for IRPA-ADP/collagen : OR = 4.5 , 95 % CI 1.2 to 16.9 , p<0.05 ) . Conclusions : The data suggest that ACS is independently associated with IRPA despite conventional antiplatelet therapy . Further studies are warranted to demonstrate the effects of intensified antiplatelet therapy for patients with acute coronary events OBJECTIVE — Diabetic patients may have a higher prevalence of platelet aspirin resistance than nondiabetic patients . Our goal was to analyze platelet aspirin responsiveness to various aspirin doses in diabetic and nondiabetic patients . RESEARCH DESIGN AND METHODS — We examined the effect of aspirin ( 81 , 162 , and 325 mg/day for 4 weeks each ) on platelet aspirin responsiveness in 120 stable out patients ( 30 diabetic patients and 90 nondiabetic patients ) with coronary artery disease ( CAD ) using light transmittance aggregometry ( LTA ) , VerifyNow , platelet function analyzer (PFA)-100 , and levels of urinary 11-dehydro-thromboxane B2 ( 11-dh-TxB2 ) . RESULTS — In the total group , a low prevalence ( 0–2 % ) of aspirin resistance was observed with all aspirin doses as determined by arachidonic acid – induced LTA . Aspirin resistance was higher at the 81-mg dose in diabetic versus nondiabetic patients using collagen-induced LTA ( 27 vs. 4 % , P = 0.001 ) , VerifyNow ( 13 vs. 3 % , P = 0.05 ) , and urinary 11-dh-TxB2 ( 37 vs. 17 % , P = 0.03 ) . Diabetic patients treated with 81 mg exhibited higher platelet function measured by VerifyNow , collagen- and ADP-induced LTA , and 11-dh-TxB2 levels ( P ≤ 0.02 for all comparisons ) . Higher aspirin doses significantly inhibited platelet function and decreased aspirin resistance in diabetic patients ( P < 0.05 ) . CONCLUSIONS — Diabetic patients with CAD treated with 81 mg aspirin exhibit a higher prevalence of aspirin resistance and have significantly higher ADP- and collagen-induced platelet aggregation , 11-dh-TxB2 levels , and aspirin reaction units measured by VerifyNow than nondiabetic patients . Increased aspirin dosing result ed in similar rates of resistance and platelet function levels between groups . These findings indicate that diabetic patients exhibit a global high platelet reactivity phenotype that may be partially overcome by higher aspirin doses Aspirin and clopidogrel are proven to prevent thromboembolic events during percutaneous coronary intervention ( PCI ) . Enzyme release of creatine kinase-MB ( CK-MB ) enzyme during PCI has been associated with an increased risk of future adverse cardiac events . This study examined the correlation between measurements of aspirin resistance and the level of inhibition of the thienopyridine-specific P2Y12 platelet receptor and CK-MB release after PCI . We prospect ively studied 330 patients with elective PCI treated with drug-eluting stents . Patients were pretreated with aspirin and clopidogrel . Patients with positive CK-MB or acute coronary syndrome and those on glycoprotein IIb/IIIa inhibitors were excluded .  Serum assays of aspirin resistance  ( Ultegra Rapid Platelet Function Assay-ASA , Accumetrics ) and  clopidogrel resistance  ( Rapid Platelet Function Assay P2Y12 , Accumetrics ) were performed before PCI . Serum troponinI and CK-MB levels were measured at 8 , 16 , and 24 hours after PCI . Aspirin resistance unit ( ARU ) measurement > or = 550 was detected in 12 patients ( 3.7 % ) . Mean platelet reactivity unit ( PRU ; measurement of inhibition of P2Y12 activity ) was 192.2 + /- 95.4 ( lower PRU , more inhibition of P2Y12 receptor ) . There was no correlation between level of ARU or PRU and troponin I or CK-MB release after PCI at any time point . Only multivessel coronary disease was found to be a predictor of any increase in CK-MB in a multivariate analysis ( odds ratio 2.2 , 95 % confidence interval 1.4 to 3.3 , p = 0.0003 ) . A positive correlation was found between levels of ARU and PRU . Target vessel revascularization/major adverse cardiac event rate at 6 months was 8.2 % with no correlation between ARU or PRU and release of cardiac enzymes or occurrence of adverse cardiac events . In conclusion , this study does not support routine measurements of aspirin and clopidogrel resistance in stable patients undergoing PCI We determined the prevalence and clinical predictors of aspirin resistance by prospect ively study ing 325 patients with stable cardiovascular disease who were receiving aspirin ( 325 mg/day for > or = 7 days ) but no other antiplatelet agents .  We also compared the detection of aspirin resistance with optical platelet aggregation , a widely accepted method , with a newer , more rapid method , the platelet function analyzer (PFA)-100 , a whole blood test that measures platelet adhesion and aggregation ex vivo . Blood sample s were analyzed in a blinded fashion for aspirin resistance by optical aggregation using adenosine diphosphate ( ADP ) and arachidonic acid , and by PFA-100 using collagen and /or epinephrine and collagen and /or ADP cartridges to measure aperture closure time . Aspirin resistance was defined as a mean aggregation of > or = 70 % with 10 microM ADP and a mean aggregation of > or = 20 % with 0.5 mg/ml arachidonic acid . Aspirin semiresponders were defined as meeting one , but not both of the above criteria . Aspirin resistance by PFA-100 was defined as having a normal collagen and /or epinephrine closure time ( < or = 193 seconds ) . By optical aggregation , 5.5 % of the patients were aspirin resistant and 23.8 % were aspirin semiresponders . By PFA-100 , 9.5 % of patients were aspirin resistant . Of the 18 patients who were aspirin resistant by aggregation , 4 were also aspirin resistant by PFA-100 . Patients who were either aspirin resistant or aspirin semiresponders were more likely to be women ( 34.4 % vs 17.3 % , p = 0.001 ) and less likely to be smokers ( 0 % vs 8.3 % , p = 0.004 ) compared with aspirin-sensitive patients . There was a trend toward increased age in patients with aspirin resistance  or aspirin semiresponders ( 65.7 vs 61.3 years , p = 0.06 ) . There were no differences in aspirin sensitivity by race , diabetes , platelet count , renal disease , or liver disease OBJECTIVES Although the concept of aspirin resistance is extensively reported in medical literature , its precise mechanisms and clinical outcomes are largely unknown . In this study , we examined individual thromboxane bio synthesis and platelet aggregation in  aspirin-treated patients , and whether the results of a platelet aggregation test influenced clinical outcomes . RESULTS Subjects taking 81 mg of aspirin ( n = 50 ) and controls ( n = 38 ) were evaluated for platelet aggregation and platelet cyclooxygenase-1 ( COX-1 ) activity by measuring collagen-induced thromboxane B2 production . For aggregometry , both light transmission ( LT ) and laser-light scattering methods were employed to quantitatively evaluate aggregate sizes and numbers .  Aspirin treatment result ed in the inhibition of collagen-induced platelet aggregation , particularly the transition from small to large platelet aggregates . Although platelet COX-1 activity seemed to be uniformly inhibited in all patients , platelet aggregation studies showed great inter-individual differences ; variation in platelet COX-1 activity only accounted for 6 - 20 % of the individual aggregations . Factor analysis revealed the existence of a common factor ( other than platelet COX-1 ) that explained 48.4 % of the variations in platelet aggregation induced by collagen , adenosine diphosphate ( ADP ) , and collagen-related peptide . We then prospect ively enrolled 136 aspirin-treated patients in our study , and we found that being in the upper quartile level of LT , or with large aggregate formation induced by collagen , was an independent risk factor for developing cardiovascular events within 12 months [ hazard ratio ( HR ) = 7.98 , P = 0.008 for LT ; HR = 7.76 , P = 0.007 for large aggregates ] . On the other h and , the existence of diabetes mellitus was an independent risk factor for overall outcomes ( HR 1.30 - 11.9 , P = 0.015 - 0.033 ) . CONCLUSIONS Aspirin resistance expressed as unsuppressed platelet COX-1 activity is a rare condition in an out-patient population . Other factor(s ) affecting collagen-induced platelet aggregation may influence early outcomes in aspirin-treated patients Although the platelet aggregation test is the most common method for evaluating response to antiplatelet therapy , little is known about the association of recurrent cerebral infa rct ion with platelet aggregation in the presence of various different antiplatelet drugs . We prospect ively evaluated adenosine diphosphate (ADP)- and collagen-induced platelet aggregation and followed the incidence of recurrent infa rct ion in patients categorized into 3 groups based on treatment ; aspirin ( n = 144 ) , ticlopidine ( n = 100 ) , and aspirin + ticlopidine ( n = 96 ) . The patients in each treatment group were stratified into quartiles according to platelet aggregation , and the association of recurrent infa rct ion with platelet aggregation was investigated . ADP-induced platelet aggregation values were significantly lower in the ticlopidine group and the aspirin + ticlopidine group compared with the aspirin group ( P < .001 ) , and collagen-induced platelet aggregation values were significantly lower in the aspirin group and the aspirin + ticlopidine group compared with the ticlopidine group ( P < .001 ) . In the aspirin group , the recurrence rate was somewhat higher in the higher aggregation quartiles than in the lower aggregation quartiles of 2 μg/mL collagen , the differences were not statistically significantly ( P = .243 ) . In the ticlopidine group , the recurrence rate was significantly higher in the lower aggregation quartiles compared with the higher aggregation quartiles of 1 μmol/L ADP ( P = .025 ) . No tendencies were found in the aspirin + ticlopidine group . Although the study is limited by its small sample size , the results suggest a possible difference between aspirin therapy and ticlopidine therapy in the pattern of association of recurrent infa rct ion with platelet aggregation Previous studies have shown that more complete platelet inhibition improves the coronary flow reserve ( CFR ) , a measure of microvascular integrity , in patients undergoing percutaneous coronary intervention ( PCI ) . We hypothesized that patients with aspirin resistance would have impaired CFR after elective PCI . We used VerifyNow Aspirin to determine the response to aspirin in 117 consecutive patients who underwent elective single-lesion PCI . The assay results are expressed quantitatively in Aspirin Reaction Units based on the degree of platelet aggregation . All patients received a 300-mg loading dose of clopidogrel > 12 hours before and a 75-mg maintenance dose the morning of PCI . CFR was estimated using the Thrombolysis In Myocardial Infa rct ion frame count method . Of the 117 patients , 22 ( 18.8 % ) were aspirin resistant . The clinical , angiographic , and procedural characteristics of the aspirin-sensitive and -resistant patients were balanced . All patients underwent successful PCI with < 50 % residual diameter stenosis and Thrombolysis In Myocardial Infa rct ion grade 3 flow after PCI . Aspirin-resistant patients had a lower CFR than the aspirin-sensitive patients ( 1.42 + /- 0.35 vs 1.80 + /- 0.64 , p = 0.018 ) . Univariate correlates of CFR included the Aspirin Reaction Unit ( r = -0.227 , p = 0.014 ) and post-PCI creatine kinase-MB elevation ( p = 0.048 ) . Multivariate linear regression analysis revealed the Aspirin Reaction Unit to be the only independent determinant of CFR after PCI ( r2 = 0.051 , p = 0.014 ) . Thus , aspirin resistance was associated with impaired CFR in patients who underwent elective PCI , implicating insufficient aspirin-induced platelet inhibition as a cause of microvascular dysfunction by distal atherothrombotic embolization and /or spasm OBJECTIVE To investigate the occurrence of aspirin resistance in coronary heart disease ( CHD ) patients and its influence on myonecrosis among patients undergoing non-emergent percutaneous coronary intervention ( PCI ) . METHODS 256 CHD patients who have been on aspirin ( 100 mg/d ) for at least 7 days were recruited based on  aspirin responsiveness determination . All the patients were divided into two groups : aspirin-resistant group and aspirin-sensitive group . For all patients scheduled for non-emergent PCI , a loading dose of 300 mg of clopidogrel was given at least 12 h before PCI and a 75 mg maintenance dose was given every morning before and after PCI . The incidence of myonecrosis was evaluated by the levels of creatine kinase-myocardial b and ( CK-MB ) and troponin I ( TnI ) before and after PCI . RESULTS Aspirin resistance was found in 67 ( 26.2 % ) patients and 189 ( 73.8 % ) patients were aspirin-sensitive . There was a significantly higher proportion of female subjects in the aspirin-resistant group . The incidence of any CK-MB elevation was 38 ( 56.7 % ) in aspirin-resistant group and 42 ( 22.2 % ) in aspirin-sensitive group ( P < 0.01 ) . The elevation of TnI was observed in 41 ( 61.2 % ) of the aspirin-resistant group and in 67 ( 35.4 % ) of the aspirin-sensitive group ( P < 0.05 ) . Multivariate analysis revealed that aspirin resistance was an independent predictor for CK-MB elevation after PCI ( OR = 2.5 ; 95 % CI 1.5 to 6.5 ; P < 0.05 ) . CONCLUSION Aspirin resistance exists in some CHD patients , which increases the risk of myonecrosis following non-emergent PCI OBJECTIVE The presence of the glycoprotein IIIa allele PlA2 is associated with enhanced thrombin formation and an impaired antithrombotic action of aspirin , which could favor coronary thrombosis . We wondered whether PlA1/A2 genetic polymorphism could affect the postoperative bleeding in patients undergoing coronary artery bypass grafting .  We also aim ed to assess the effects of aspirin pretreatment and to ascertain the value of platelet function studies as predictors of postoperative bleeding . METHODS In a r and omized , double-blind study , patients undergoing coronary artery bypass grafting were pretreated with a 150-mg dose of aspirin orally 12 and 3 hours before surgery ( n = 51 , 41 elective ) or with placebo ( n = 51 , 43 elective ) . The hemostasis was monitored by Simplate ( bioMérieux , Inc , Durham , NC ) bleeding time and capillary closure time ( platelet function analyzer PFA 100 ; Sysmex UK Ltd , Milton Keynes , United Kingdom ) . Postoperative bleeding and blood products transfusions were recorded . The glycoprotein IIIa polymorphism was analyzed . RESULTS Bleeding was significantly greater in PlA1 homozygotes from control group . Blood loss was significantly greater ( by 25 % ) in aspirin group . The volume of blood products transfusions in aspirin patients was significantly larger ( by 137 % ) . When subjects were stratified accordingly to blood platelet glycoprotein IIb/IIIa genotype , in the aspirin group PlA2 carriers had greater blood loss than PlA1 homozygotes ( 1858 + /- 932 mL vs 1216 + /- 525 mL , P < .05 ) . CONCLUSION PlA1 homozygotes normally had a greater risk of perioperative bleeding . Capillary closure time had no advantage relative to Simplate bleeding time in predicting postoperative blood loss . Aspirin pretreatment revealed no beneficial effects and result ed in increased postoperative bleeding and requirement for blood product transfusions after coronary artery bypass grafting in patients with stable angina . It was most unfavorable for PlA2 carriers The hypothesis that aspirin resistance is often due to noncompliance was investigated . One hundred ninety patients with a history of myocardial infa rct ion were evaluated using arachidonic acid-stimulated light aggregometry at 3 different time points : while receiving their usual daily aspirin , after not receiving aspirin for 7 days , and 2 hours after the observed ingestion of aspirin 325 mg . At the first time point , 17 patients ( 9 % ) failed to show  aspirin inhibition of platelet aggregation , but 2 hours after observed aspirin ingestion ,  aspirin inhibition was observed in all but 1 patient 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 Low-response to the P2Y12 adenosine diphosphate (ADP)-receptor antagonist clopidogrel was suggested to correspond to a higher incidence of stent thrombosis ( ST ) . This prospect i ve observational study assessed the capability of two platelet function assays , e.g. direct measurement of the phosphorylation status of vasodilator-stimulated phosphoprotein ( VASP ) and ADP-induced platelet aggregation for definition of the individual risk to develop ST . Ninety-nine patients with an elevated high risk to develop ST were enrolled . All patients received a dual antiplatelet therapy consisting of 100 mg aspirin and 75 mg clopidogrel during an observation period of six months . Flow cytometry of VASP phosphorylation and densitometrically-determined measurement of ADP-induced platelet aggregation was performed 72 - 96 hours after stent implantation . These data were related to angiographically confirmed ST . Nine patients suffered from angiographically confirmed ST ( 9.1 % ) . The meanVASP-platelet reactivity indices ( VASP-PRI ) and values for ADP-induced platelet aggregation in the ST group were significantly higher ( 60.8 + /- 13.0 and 60.9 + /- 13.1 , respectively ) compared to patients without ST ( 41.3 + /- 14.0 and 50.8 + /- 14.4 , P < 0.001 vs. 0.048 , respectively ) . There was a fair correlation between both methods using non-linear regression analysis ( r = 0.332 ) . In a multivariate analysis , VASP was the only independent predictor of ST and was superior to previously identified angiographic parameters . Receiver- operator characteristic ( ROC ) curve analysis revealed a cut-off value for VASP-PRI of < 48 % to be associated with low risk of ST . In conclusion , determination of VASP phosphorylation is superior to conventional platelet aggregometry and angiographic parameters for assessing the risk of ST . Patients with a VASP-PRI > 48 % seem to have a significantly increased risk Objective To assess whether prehospital initiation of high-dose tirofiban in addition to high-dose clopidogrel results in more adequate inhibition of platelet aggregation ( IPA ) and better clinical outcome after primary percutaneous coronary intervention ( PCI ) . Methods Prespecified two-centre sub study of the prospect i ve , international , multicentre , placebo controlled Ongoing Tirofiban in Myocardial Infa rct ion Evaluation trial 2 ( On-TIME-2 trial ) . 648 of 964 ( 67 % ) patients in the On-TIME-2 trial with ST elevation myocardial infa rct ion undergoing primary PCI were studied . Pre-PCI IPA after early prehospital initiation of high-bolus dose ( 25 μg/kg ) tirofiban was compared to placebo in addition to acetylsalicylic acid , unfractionated heparin and 600 mg clopidogrel .  Results IPA was measured at a median of 60 min after study medication administration . In all four tests : Fe induced platelet aggregation , ADP induced platelet aggregation , platelet function analyser (PFA)-100 ( collagen – epinephrine and collagen – ADP cartridge ) IPA was higher in patients pretreated with high-dose tirofiban ( p<0.001 for all tests ) , even after > 74 min of pretreatment . Patients in the highest quartile of IPA had less residual ST segment deviation 1 h post-PCI ( p value for trend : p=0.001 , 0.004 , 0.001 , 0.002 respectively ) . There was a significant relationship between PFA-100 ( both cartridges ) and major adverse cardiovascular events ( MACE , p=0.028 , p=0.035 ) and early thrombosis ( p=0.009 , p=0.007 ) . Conclusions 60 min of prehospital initiated antiplatelet treatment including high-dose tirofiban result ed in higher levels of IPA compared to pretreatment with acetylsalicylic acid and high-dose clopidogrel alone , even after longer pretreatment times . Levels of IPA were significantly related to ST resolution and MACE , including stent thrombosis . This sub study confirms the main findings of the On-TIME2 trial that clopidogrel alone is suboptimal , even at high dose and administered well in advance of primary PCI Background Long-term success in ventricular assist device ( VAD ) recipients is limited by thromboembolic events , the prediction of which remains elusive . We evaluated the predictive value of aspirin hyporesponsiveness and markers of coagulation and fibrinolysis . Methods We prospect ively enrolled patients scheduled to undergo VAD implantation between June 2004 and March 2006 . Once before surgery , daily during hospitalization , and weekly after discharge we assessed platelet function , measured prothrombin activation fragment 1.2 ( F1.2 ) and plasminogen activator inhibitor-1 ( PAI-1 ) concentrations , and evaluated  aspirin hyporesponsiveness by whole-blood aggregometry and thromboelastography . All patients received 325 mg oral aspirin daily from at least 7 days before VAD implantation . Follow-up continued until heart transplantation , death or closure of the data base . Results We included 26 patients ( median follow-up 315 days , range 9–833 days ) . In eight ( 31 % ) patients , 14 thromboembolic events occurred at a median of 42 ( interquartile range 26–131 ) days . Only six ( 43 % ) events based on whole-blood aggregometry and one ( 7 % ) based on thromboelastography coincided with aspirin hyporesponsiveness . Within-patient variability was high for both tests ( 59 % and 567 % , respectively ) . Compared with levels before surgery , PAI-1 concentrations were raised for up to 45 days ( P < 0.0001 ) and those of F1.2 for up to 3 days ( P = 0.0001 ) after VAD implantation . PAI-1 and F1.2 levels did not rise significantly further before thromboembolic events . Conclusions Aspirin hyporesponsiveness was not associated with raised risk of future clinical thromboembolic events after VAD implantation . Impaired fibrinolysis , demonstrated by raised PAI-1 concentrations , might , however , indicate a predisposition to such events early after surgery Objective Previous studies have demonstrated significant heterogeneity in responses to antiplatelet therapy ( APT ) , and high residual platelet reactivity is associated with the risk of ischaemic events , including stent thrombosis ( ST ) . The prevalence of APT hyporesponsiveness in a ‘ real world ’ registry of ST patients and the feasibility of personalising APT are reported . Patients and setting 39 consecutive patients admitted to a single regional cardiothoracic centre with definite ST were prospect ively evaluated . Interventions Response to aspirin and clopidogrel  was measured following discharge using  short thrombelastography ( TEG ) , a rapid , well vali date d near patient platelet function test . Treatment modification in hyporesponders comprised an increase in aspirin dose and /or changing clopidogrel to prasugrel or ticagrelor . Short TEG was repeated following treatment modification to ensure an adequate response had been achieved . Results 12 ( 31 % ) patients had an adequate response to both aspirin and clopidogrel  , 16 ( 41 % ) were hyporesponsive to clopidogrel alone , one ( 3 % ) was hyporesponsive to aspirin alone and 10 ( 26 % ) were hyporesponsive to both aspirin and clopidogrel . Following treatment modification , an adequate response to aspirin and P2Y12 agent was achieved in 10 ( 91 % ) and 22 ( 85 % ) patients , respectively . None has presented with a further ST episode . Conclusions There is a high prevalence of hyporesponsiveness to APT in patients with ST . Improved APT efficacy can be achieved by tailored therapy . Short TEG is a plausible platelet function test that can be used to deliver point of care personalised APT The primary objective of this study was to apply a sophisticated coagulation monitoring system including estimation of the concentration of  prothrombin fragment 1 + 2 ( PTF 1 + 2 ) and the activity of prothrombin ( coagulation factor II or FII ) to cases of stent implantation and to compare the results with those of st and ard coagulation tests . The secondary objective was to detect the incidence after stenting of subacute thrombosis ( SAT ) and bleeding complications in these patients and to compare the results with those of a group of patients with stent implantation in whom coagulation was monitored exclusively by st and ard tests .  SAT several days after coronary stenting occurs in up to 20 % despite aggressive intravenous and overlapping oral anticoagulation . According to a prospect i ve study protocol 120 consecutive patients with implantation of 155 Palmaz-Schatz stents  underwent coagulation monitoring including single daily estimation of the  concentration of PTF1 + 2 ( target range < 0.5 nmol/L ) and of  FII activity  ( 15 % to 35 % ) in addition to the st and ard tests of thrombin time ( TT ) , partial thromboplastin time ( aPTT ) , international normalized ratio ( INR ) , antithrombin III ( ATIII ) , and fibrinogen . Adjustment of heparin and phenprocoumon dosages in this study group was based only on the results of PTF1 + 2 and FII measurements . A control group consisted of 53 patients with implantation of 64 stents who were matched for baseline , angiographic , and procedure-related characteristics . After stenting , anticoagulation was monitored by estimation of TT ( target range > 70 seconds ) , aPTT ( > 70 seconds ) , INR ( 3.0 to 4.5 ) , AT III ( > 80 % ) , and fibrinogen ( < 450 mg/dl ) in this control group . There was a weak correlation between PTF1 + 2 and aPTT ( r = 0.337 ; PTF1 + 2 = -0.00169aPTT + 0.491 ) and PTF1 + 2 and TT ( r = 0.328 ; PTF1 + 2 = -0.00142TT + 0.494 ) . A better correlation was found between FII and INR ( r = 0.983 ; FII = -23.8 INR + 134 ) . Stable oral anticoagulation was maintained 2.8 + /- 0.9 days later according to an FII concentration of < 35 % compared with an INR > 3 . The incidence of SAT was 3.3 % with 3.0 % for elective versus 3.8 % for nonelective stenting . The sensitivity , specificity , and accuracy of the PTF1 + 2 test were 100 % , 88 % , and 88 % , respectively . In the control group the incidence of SAT was 17 % , with 16.1 % for elective versus 18 % for nonelective stenting . Major bleeding complications occurred in 10 % ( study group ) and in 11.3 % ( control group ) of patients ( no statistical difference ) . ( ABSTRACT TRUNCATED AT 400 WORDS Platelet – leukocyte conjugates are increased in patients with coronary artery disease but the relationship between conjugate formation and myocardial ischemic outcome is unknown . We prospect ively evaluated the relationship between conjugate formation and the development of recurrent myocardial ischemia in patients with acute coronary syndromes ( ACS ) . Platelet – leukocyte conjugate formation ( induced by thrombin receptor activating peptide ( TRAP ) ) and platelet aggregation ( induced by ADP and arachidonic acid ) were assessed in 30 patients with unstable angina or non-ST elevation myocardial infa rct ion . All patients were treated with β-blockers , aspirin , heparin , and GPIIb – IIIa antagonists and were followed for in-hospital recurrent myocardial ischemia . Troponin I and C-reactive protein ( CRP ) were also measured . Seven patients ( 23 % ) experienced recurrent ischemia . Platelet – neutrophil conjugates were greater in ischemic patients ( 59 ± 9 and 36 ± 4 % , P = 0.007 , for + ischemia and −ischemia , respectively ) . Platelet aggregation did not differ between ischemic and nonischemic patients , and there was no significant relationship between aspirin resistance and ischemic outcome . Troponin I was greater in patients who developed recurrent ischemia ( 3.04 ± 1.73 vs. 0.70 ± 0.21 ng/ml , P = 0.03 , for + ischemia and −ischemia , respectively ) but CRP was not . TRAP-induced platelet – neutrophil conjugate formation was an independent predictor of ischemic outcome ( OR 1.07 , 95 % CI 1.00–1.15 , for each 1 % increase in conjugate formation ) . Receiver operator characteristic analysis showed platelet – neutrophil conjugates to have good ability to discriminate between ischemic and nonischemic patients ( AUC of 0.84 , P<0.05 ) . TRAP induced platelet – neutrophil conjugate formation is related to in vivo ischemic risk in ACS patients AIM Previous studies regarding on-treatment platelet reactivity have focused on response variability to individual antiplatelet agents . There are limited data on [ 1 ] response variability to both of these anti-platelet drugs , [ 2 ] efficacy of combining two point-of-care tests ( POCT ) simultaneously and [ 3 ] how it predicts the clinical outcome after percutaneous coronary intervention ( PCI ) . METHODS We analyzed 716 patients , enrolled in the CILON-T prospect i ve r and omized controlled trial , with both VerifyNow P2Y12 ( PRU ) and Aspirin ( ARU ) data at discharge . Patients were classified according to the tertile of PRU , ARU and the sum of the tertiles of PRU and ARU . The primary endpoint was the composite of cardiac death , nonfatal myocardial infa rct ion ( MI ) and ischemic stroke at 6 months post-PCI . RESULTS Ten patients reached the primary endpoint , four of which were nonfatal MI and six ischemic stroke . When analyzed for the primary endpoint , tertiles of ARU and PRU were not able to discriminate patients with future thrombotic events from the remainder ( p= 0.197 for ARU and 0.058 for PRU with the log-rank test , respectively ) , whereas combining the tertiles of ARU and PRU was significantly effective ( p= 0.019 for ARU+PRU with the log-rank test ) . Multivariate analysis showed that the highest tertile of the sum of ARU and PRU tertiles was the only significant predictor of future thrombotic events after PCI ( HR 6.34 , 95 % confidence interval 1.32 - 30.47 , p= 0.021 ) . CONCLUSIONS In this post-hoc analysis of the CILON-T trial , combining the results of ARU and PRU simultaneously had a significant role in discriminating patients at highest risk of future thrombotic events after PCI compared with either assay alone BACKGROUND Some data suggest that biological ' resistance ' to aspirin or clopidogrel may influence clinical outcome . OBJECTIVE The aim of this study was to evaluate the relationship between aspirin and clopidogrel responsiveness in healthy subjects . METHODS Ninety-six healthy subjects were r and omly assigned to receive a 1-week course of aspirin 100 mg day(-1 ) followed by a 1-week course of clopidogrel ( 300 mg on day 1 , then 75 mg day(-1 ) ) , or the reverse sequence , separated by a 2-week wash-out period . The drug effects were assessed by means of serum TxB2 assay , platelet aggregation tests , and the PFA -100 and Ultegra RPFA -Verify Now methods . RESULTS Only one subject had true aspirin resistance , defined as a serum TxB2 level > 80 pg microL(-1 ) at the end of aspirin administration and confirmed by platelet incubation with aspirin . PFA-100 values were normal in 29 % of the subjects after aspirin intake , despite a drastic reduction in TxB2 production ; these subjects were considered to have aspirin pseudo-resistance . Clopidogrel responsiveness was not related to aspirin pseudo-resistance . Selected polymorphisms of platelet receptor genes were not associated with either aspirin or clopidogrel responsiveness . CONCLUSIONS In healthy subjects , true aspirin resistance is rare and aspirin pseudo-resistance is not related to clopidogrel responsiveness BACKGROUND Decreased responsiveness to oral antiplatelet drug therapy has been associated with an adverse outcome after coronary stenting ( CS ) , but more studies are needed . The purpose of the present study was to prospect ively evaluate this issue . METHODS A total of 612 consecutive patients with stable or unstable coronary artery disease who underwent CS after at least 12 hours of aspirin and clopidogrel loading were studied . The study population was divided into responders and nonresponders to oral antiplatelet therapy , according to the values of preprocedural Platelet Function Analyzer-100 ( Dade Behring , Marburg , Germany ) collagen epinephrine closure time ( CEPI-CT ) . In particular , responders were considered as patients with a CEPI-CT > 193 seconds and nonresponders as those with a CEPI-CT < or = 193 seconds . The 1-year incidence of the composite of cardiac death and rehospitalization for nonfatal myocardial infa rct ion was the prespecified primary study end point . RESULTS At 1 year , 9.1 % of patients reached the primary end point . Nonresponders to oral antiplatelet therapy were at significantly higher risk for the primary end point ( 18.7 % vs 7.6 % ) than responders . Nonresponsiveness to oral antiplatelet therapy  was a predictor of the primary end point by both univariate ( hazard ratio 2.7 , 95 % CI 1.6 - 4.5 , P < .001 ) and multivariate ( hazard ratio 2.5 , 95 % CI 1.6 - 3.8 , P < .001 ) Cox regression analysis . CONCLUSION Based on the present data , preprocedural responsiveness to oral antiplatelet therapy , assessed by Platelet Function Analyzer-100 CEPI-CT , is an independent predictor of long-term outcome after CS AIM The relationships between clinical events and acetylsalicylic acid resistance ( AR ) , as well as its frequency , have been established in stable patients with coronary artery disease ( CAD ) . Although acute coronary syndrome ( ACS ) patients taking  acetylsalicylic acid  have been accepted as a high-risk population , the role of AR has not been investigated in these patient groups . Thus , in the present study , the impact of AR was investigated in patients with ACS who were taking acetylsalicylic acid .  METHODS Between January 2001 and February 2003 , 140 ACS patients were included in the present prospect i ve study . All patients had ACS while taking acetylsalicylic acid .  Coronary angiographic scores for severity and extent of CAD were determined for all patients . The effect of acetylsalicylic acid on platelet function was assessed by the platelet function analyzer PFA-100 ( Dade Behring , USA ) . The primary end point was the composite of death , myocardial infa rct ion , cerebrovascular accident and revascularization . The mean follow-up period was 20 months . RESULTS Patients with AR were  older  than patients without AR ( 63.8+/-10.8 years versus 58.3+/-11.2 years ; P=0.005 ) . Moreover , myocardial damage was higher in patients with AR according to cardiac troponin T values ( 1.11+/-1.3 mug/L versus 0.41+/-0.5 mug/L ; P=0.01 ) . The composite end point of death , myocardial infa rct ion , cerebrovascular accident or revascularization was present in 16 of 45 patients ( 35 % ) with AR and in 13 of 79 patients ( 16 % ) without AR ( hazard ratio 2.46 , 95 % CI 1.18 to 5.13 ; P=0.016 ) . After adjustment for age , platelet count , cardiac troponin T value and CAD severity score , AR remained an independent predictor for long-term adverse events ( hazard ratio 3.03 , 95 % CI 1.06 to 8.62 ; P=0.038 ) . CONCLUSIONS The clinical event rate was found to be higher in ACS patients with AR than in those without AR . Thus , it may be concluded that there is a strong correlation between a worse prognosis and AR in these patients Abstract Aim : To estimate the cost of treating stroke in the UK . Methods : A cost-of-illness model was constructed to estimate stroke-related costs over a 5-year period . The cost estimates were based on data from a large , r and omised , prospect i ve study comparing alternative strategies of stroke care . The study collected detailed data on re source use in hospital , primary care , healthcare contacts , and utilisation of social services over a period of 1 year following stroke . A Markov framework was used to extrapolate 1-year costs over 5 years . Results : The model estimated that , for every patient who experiences a stroke , the cost to the NHS in the UK is £ 15 306 over 5 years and , when informal care costs are included , the amount increases to £ 29 405 ( 2001/2002 prices ) . The robustness of the cost findings was explored with the use of sensitivity analysis . This focused on the key variables of rates of recurrent stroke , the estimated acute costs , and costs attached to institution and home care . Conclusion : As well as being a considerable cause of morbidity and mortality , stroke is also a huge cost burden to both the UK ’s NHS and the carers of stroke victims BACKGROUND AND PURPOSE Biological aspirin resistance ( AR ) has been recognized as an important cause of clinical AR . Recent studies have reported the beneficial effects of cilostazol for the prevention of cardiovascular diseases . This study investigated whether addition of cilostazol to aspirin in ischaemic stroke patients can reduce AR . METHODS In this double-blind multicenter trial , 244 aspirin users with ischaemic stroke were r and omly assigned to receive cilostazol 100 mg twice daily or to placebo .  Antiplatelet function was assessed using the VerifyNow Aspirin system . The primary end-point was the incidence of AR , which was measured as aspirin resistance unit ( ARU ) > or = 550 after 4-week treatment . RESULTS The incidence of AR after treatment in cilostazol group was not significantly different from that in placebo ( 8.8 % vs. 10.9 % , P = 0.578 ) . However , AR decreased from 12.8 % to 8.8 % in cilostazol group , whereas it was not changed in the placebo group . The mean ARU after treatment were also lower in the cilostazol group ( 456.9 + /- 56.0 vs. 470.7 + /- 67.2 , P = 0.081 ) . Cilostazol addition did not prolong bleeding time . CONCLUSIONS Although this was a negative study , our findings disclosed a trend toward enhanced antiplatelet effects when cilostazol was added to aspirin in ischaemic stroke patients . Combination of aspirin and cilostazol might be a treatment option in the ischaemic stroke patients with AR A group of 100 patients with intermittent claudication ( 70 male , 30 female ) , treated with I00 mg ASA per day , were followed over 18 months after elective percutaneous balloon angioplasty .  Platelet function was monitored over a period of 12 months by corrected whole blood aggregometry ( CWBA ) . Upon stimulation by arachidonic acid ( AA ) , adenosine diphosphate ( ADP ) and collagen , CWBA- results were obtained by an electronic acquisition and evaluation system correcting for hematocrit and platelet count of the blood sample . All patients showed a completely inhibited platelet response to AA stimulation . Comparison of the CWBA- results with clinical parameters revealed that reocclusions at the site of angioplasty occurred exclusively in male patients for which CWBA failed to prove an inhibition of aggregation upon both agonists , ADP and collagen , and for these patients the risk of complication is at least 87 % higher ( p = 0.0093 ) . Only 40 % of male patients show the expected effect of ASA on in vitro platelet aggregation at any given point in time and CWBA is capable of predicting those male patients which are at an elevated risk of reocclusion following peripheral angioplasty Celecoxib is a novel cyclooxygenase-2-specific inhibitor for the management of acute pain , primary dysmenorrhea , and the signs and symptoms of arthritis . This double-blind , placebo-controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function . Volunteers received celecoxib ( 400 mg/day ) or placebo for 4 days . On day 5 , they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo .  Thromboxane and platelet aggregation response to adenosine 5'-diphosphate ( ADP ) , collagen , and arachidonic acid were measured before the first dose of celecoxib or placebo ( baseline ) and before dosing and 2 and 8 hours post dose on day 5 . There was no significant difference in thromboxane inhibition between the two groups ( percent inhibition : placebo 99.4 % , celecoxib 99.0 % ; p = 0.555 ) . There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP , collagen , or arachidonic acid between the groups . Therefore , these data indicate that celecoxib does not alter the effects of aspirin on platelet function 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 Platelets , long believed to be incapable of de novo protein synthesis , may retain their ability to form the cyclooxygenase ( COX ) enzyme once it has been inactivated by aspirin . This may explain the inefficacy of the drug to induce sustained platelet inhibition in certain patients . We evaluated the stability of platelet inhibition following once-daily enteric-coated aspirin administration . METHODS Platelet responsiveness to aspirin was evaluated in 11 stable coronary artery disease patients on chronic aspirin therapy before and 1 , 3 , 8 , and 24h after observed ingestion of 80-mg enteric-coated aspirin . Inhibition of the COX pathway was measured pharmacologically through plasma thromboxane ( Tx ) B(2 ) levels , and functionally by light transmission aggregometry in response to arachidonic acid . COX-independent platelet activity was measured in response to adenosine diphosphate , epinephrine and collagen . RESULTS Plasma TxB(2 ) levels showed profound inhibition of TxA(2 ) formation , which was stable throughout 24h , in all but 1 subject . This subject had optimal response to aspirin ( inhibition of platelet TxA(2 ) production within 1h ) , but recovered the ability to synthesize TxA(2 ) within 24h of aspirin ingestion . Arachidonic acid-induced platelet aggregation closely mirrored TxB(2 ) formation in this patient , portraying a functional ability of the platelet to aggregate within 24h of aspirin ingestion . COX-independent platelet aggregation triggered TxA(2 ) production to a similar extent in all patients , likely through signal-dependent protein synthesis . CONCLUSIONS COX-dependent platelet activity is recovered in certain individuals within 24h of aspirin administration . Further research should consider increasing aspirin dosing frequency to twice daily , to allow sustained inhibition in such subjects Clinical significance of resistance to aspirin and thienopyridine therapy is poorly defined . The authors aim ed to evaluate whether more effective antiplatelet therapy is associated with better outcome in patients on dual-antiplatelet treatment . Using optical aggregometer , maximal platelet aggregation values were measured with induction of adenosine diphosphate , collagen , and adrenaline 30 ± 5 days after coronary stent implantation in 134 patients .  Markers of platelet activation were also analyzed with fluorescent immunoassay in 57 patients . After 10 months of follow-up , 33 patients reached the composite endpoint of cardiovascular death , myocardial infa rct ion , and revascularisation . Adenosine diphosphate-induced maximal aggregation values were in significant relationship with the development of major adverse cardiac events ( P < .01 ) . Level of soluble P-selectin proved to be an independent risk factor of adverse outcome ( P < .05 ) . As efficacy of thienopyridine therapy showed significant relation with clinical outcome , the authors conclude that interindividual variability in response to adenosine diphosphate-receptor antagonists may be of substantial clinical importance Platelet aggregability and fibrinolytic activity were studied repeatedly in 83 patients with reversible cerebral ischemic attacks over a median follow-up period of 26 months . Platelet hyperaggregability , defined as in vitro secondary aggregation obtained by adenosine diphosphate concentration less than or equal to 1 mumol/l , was demonstrated in 36.1 % or the patients examined 5 - 8 days after the attack , but only in 6 % of age- and sex-matched blood donors ( p less than 0.001 ) . Fibrinolytic activity was reduced in 57.8 % of the patients , as compared with 20.5 % of the controls . At the time of follow-up only 8 % of the survivors showed platelet hyperaggregability , whereas the fibrinolytic activity was still reduced in 44.4 % . Over the observation period 21.7 % of the patients had a stroke or died . No significant correlation was found between abnormalities of platelet aggregability or of fibrinolytic activity , when observed 5 - 8 days after the ischemic episode , and the subsequent risk of stroke or death . It is concluded that in patients with recent cerebral ischemic attacks the demonstration of platelet hyperaggregability or reduced fibrinolytic activity appears to be without prognostic significance OBJECTIVE This study was conducted to assess the thromboxane ( TX ) dependence of biochemical and functional indexes used to monitor the effect of low-dose aspirin . BACKGROUND Functional assays of the antiplatelet effects of low-dose aspirin variably reflect the TX-dependent component of platelet aggregation . Previous studies of aspirin resistance were typically based on a single determination of platelet aggregation . METHODS We assessed the TXB(2 ) dependence of biochemical and functional indexes , as well as their intersubject and intrasubject variability during administration of the drug and after its withdrawal in 48 healthy volunteers r and omized to receive aspirin 100 mg daily for 1 to 8 weeks . RESULTS Serum TXB(2 ) was uniformly suppressed by 99 % of baseline . Urinary 11-dehydro-TXB(2 ) , arachidonic acid-induced aggregation , and VerifyNow Aspirin  ( Accumetrics Inc. , San Diego , California ) showed stable , incomplete inhibition ( 65 % , 80 % , and 35 % , respectively ) . Adenosine diphosphate- and collagen-induced aggregation was highly variable and poorly affected by aspirin , with an apparent time-dependent reversal . Inhibition of platelet cyclooxygenase activity was nonlinearly related to inhibition of platelet aggregation . Platelet function largely recovered by day 3 post-aspirin , independently of treatment duration . With any functional assay , occasionally " resistant " subjects were found to be " responders " on previous or subsequent determinations . CONCLUSIONS Platelet cyclooxygenase activity , as reflected by serum TXB(2 ) levels , is uniformly and persistently suppressed by low-dose aspirin in healthy subjects . However , the effect of aspirin is variably detected by functional assays , potentially leading to misclassification of " responder " as " resistant " phenotypes owing to poor reproducibility of functional measurements . The nonlinearity of the relationship between inhibition of TX production and inhibition of platelet function has important clinical implication OBJECTIVES The purpose of this study was to investigate the long-term outcome after elective percutaneous coronary intervention in low-risk patients screened for aspirin and /or clopidogrel responsiveness in the 3T/2R ( Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and /or Resistance to Clopidogrel ) trial . BACKGROUND The impact of aspirin and /or clopidogrel poor response on long-term outcome is debated . METHODS  Aspirin and clopidogrel response was measured with the VerifyNow system aspirin and P2Y12 assays .  After percutaneous coronary intervention ( PCI ) , death , stroke , and myocardial infa rct ion were assessed up to 1 year . RESULTS Overall , 1,277 patients were screened , and 826 ( 65 % ) were treated with PCI . In all , 124 patients were found to be aspirin  poor responders , and there were 179 clopidogrel poor responders ( totally , 278 poor responders ) . The 1-year end point was significantly higher in poor responders as compared to full responders ( 15.8 % vs. 8.6 % , p=0.002 ) , which is principally due to more myocardial infa rct ion occurrence . At multivariable analysis , clopidogrel poor response emerged as an independent predictor ( hazard ratio : 1.15 , 95 % confidence interval : 1.03 to 1.28 ) . Receiver-operator characteristic analysis identifies≤23 of percentage of platelet inhibition and ≥208 of P2Y12 reactivity units as optimal cut offs to predict 1-year end point . Excluding periprocedural events , also peri-PCI myocardial infa rct ion , which is strongly related to aspirin/clopidogrel poor response , was an independent predictor ( hazard ratio : 1.25 , 95 % confidence interval : 1.14 to 1.37 ) . Glycoprotein IIb/IIIa inhibitor administration reduces this risk in poor responders ( 21.2 % vs. 34.7 % , p=0.02 ) , but not in full responders ( 6.3 % vs. 6.5 % , p=0.8 ) . CONCLUSIONS Poor response to clopidogrel  is an independent predictor of periprocedural myocardial infa rct ion and worse 1-year outcome in low-risk patients undergoing PCI , whereas poor response to aspirin failed to predict a worse outcome . Contrary to what was observed in poor responders , glycoprotein IIb/IIa inhibitor therapy failed to provide a benefit in aspirin and /or clopidogrel full responders Platelets play a central role in the genesis of post-percutaneous coronary intervention ( PCI ) ischemic events . High post-procedural platelet reactivity to adenosine diphosphate ( HPRADP ) may be a risk factor for ischemic events after PCI . The study was design ed to evaluate a cutpoint of platelet reactivity that is associated with the occurrence of ischemic events after PCI . Post-procedural platelet reactivity to ADP was measured by conventional aggregometry in 297 consecutive patients undergoing non-emergent PCI . Patients were prospect ively followed for up to 2 years for post-discharge ischemic events . All patients had received  clopidogrel and aspirin therapy  at the time of aggregation measurements . Eighty-one patients ( 27 % ) suffered ischemic events . Patients with ischemic events had higher 5 µM ADP-induced platelet aggregation ( 46 ± 14 % vs. 30 ± 17 % , p < 0.001 ) and 20 µM ADP-induced platelet aggregation ( 60 ± 13 % vs. 43 ± 19 % , p < 0.001 ) compared to patients without ischemic events . Using a combined receiver operator curve analysis , cutpoints of > 46 % aggregation following 5 µM ADP stimulation and > 59 % aggregation following 20 µM ADP stimulation ( HPRADP ) were associated with 58 and 54 % of ischemic events , respectively . Multivariate Cox regression demonstrated a significant relation between event occurrence and post-procedural HPRADP cutpoints ( 5 µM ADP , OR=3.9 , and 20 µM ADP , OR=3.8 , p < 0.001 for both ) . High post-procedural platelet reactivity to ADP is an independent risk factor for ischemic events within 2 years of non-emergent PCI . These data support a potential therapeutic target for antiplatelet therapy based on the results of an ex vivo platelet function test . The study is a step towards a personalized medicine approach to guide the intensity of antiplatelet therapy To determine the prevalence of platelet nonresponsiveness to aspirin treatment for secondary stroke prophylaxis , the authors studied consecutive patients during a 29-month period . Information regarding their ischemic events , risk factors , and medications was collected . Platelet aggregation in response to collagen and arachidonic acid was used to determine platelet responsiveness to aspirin .  A total of 653 patients were evaluated . Of these , 129 patients ( 20 % ) were determined to be nonresponsive to aspirin based on continued platelet aggregation in response to collagen , arachidonic acid , or both . A total of 87 ( 13 % ) of the 653 patients were clinical aspirin failures ( ie , presented with new focal cerebral ischemic symptoms while taking aspirin ) . Of the patients with new cerebral ischemic symptoms , 57 ( 66 % ) were determined to be platelet nonresponsive to aspirin . The odds ratio for platelet nonresponsiveness to aspirin  in patients who suffered a recurrent ischemic event while taking aspirin was 14.25 ( 95 % confidence interval : 8.5 - 23.7 ; P < .5 ) . Continued platelet aggregation despite  aspirin treatment occurred in 20 % of ambulatory patients treated for secondary stroke prophylaxis . The prevalence of nonresponsiveness to aspirin  was statistically higher in those patients who suffered recurrent cerebral ischemia while taking aspirin ( P < .5 ) compared with patients who remained without new ischemic symptoms
target: Results indicated that some PFTs may have some prognostic utility , i.e. a trend for more clinical events to be associated with groups classified as ' aspirin resistant ' .
  Study -level effect sizes were generally small and absolute outcome risk was not substantially different between ' aspirin resistant ' and ' aspirin sensitive ' design ations .
  Based on assumptions of PFTs being able to accurately identify patients at high risk of clinical events and such patients benefiting from treatment modification , the economic model found that a test-treat strategy was likely to be cost-effective .
  However , neither assumption is currently evidence based .
background: BACKGROUND The use of aspirin is well established for secondary prevention of cardiovascular disease .
  However , a proportion of patients suffer repeat cardiovascular events despite being prescribed aspirin treatment .
  It is uncertain whether or not this is due to an inherent inability of aspirin to sufficiently modify platelet activity .
  This report aims to investigate whether or not insufficient platelet function inhibition by aspirin ( ' aspirin resistance ' ) , as defined using platelet function tests ( PFTs ) , is linked to the occurrence of adverse clinical outcomes , and further , whether or not patients at risk of future adverse clinical events can be identified through PFTs .
  OBJECTIVES To review systematic ally the clinical effectiveness and cost-effectiveness evidence regarding the association between PFT design ation of ' aspirin resistance ' and the risk of adverse clinical outcome ( s ) in patients prescribed aspirin therapy .
  To undertake exploratory model-based cost-effectiveness analysis on the use of PFTs .