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Anti-Platelet Effects of 100 mg Alternate Day Oral Aspirin: A Randomized, Double-Blind, Placebo-Controlled Trial of Regular and Enteric Coated Formulations in Men and Women Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention. Anti-platelet drug resistance in the prediction of thromboembolic complications after neurointervention. 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 Biological efficacy of low against medium dose aspirin regimen after coronary surgery: analysis of platelet function. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. 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Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary Intervention: Results From the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance  Aspirin resistance measured by cationic propyl gallate platelet aggregometry and recurrent cardiovascular events during 4 years of follow-up. High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity Earlier application of loading doses of aspirin and clopidogrel decreases rate of recurrent cardiovascular ischemic events for patients undergoing percutaneous coronary intervention. 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Residual Arachidonic Acid–Induced Platelet Activation via an Adenosine Diphosphate–Dependent but Cyclooxygenase-1– and Cyclooxygenase-2–Independent Pathway: A 700-Patient Study of Aspirin Resistance Relation of aspirin resistance to coronary flow reserve in patients undergoing elective percutaneous coronary intervention. Platelet Aggregation and Recruitment with Aspirin-Clopidogrel Therapy 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 effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease Serial Urinary 11-Dehydrothromboxane B2, Aspirin Dose, and Vascular Events in Blacks After Recent Cerebral Infarction Prior aspirin use predicts worse outcomes in patients with non-ST-elevation acute coronary syndromes. PURSUIT Investigators. Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy. Anti-platelet effect of aspirin is substantially reduced after administration of heparin during carotid endarterectomy. Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease Effect of the Thromboxane Prostaglandin Receptor Antagonist Terutroban on Arterial Thrombogenesis after Repeated Administration in Patients Treated for the Prevention of Ischemic Stroke Effects of aspirin, clopidogrel and dipyridamole administered singly and in combination on platelet and leucocyte function in normal volunteers and patients with prior ischaemic stroke. A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone New antiplatelet therapies in development. 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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 Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention . In an earlier consensus document , we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate ( ADP ) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests ( PFTs ) . Up date d American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention , although routine testing is not recommended ( Class III ) . Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor . Recent prospect i ve r and omized trials of PFT did not demonstrate clinical benefit , thus question ing whether treatment modification based on the results of current PFT platforms can actually influence outcomes . However , there are major limitations associated with these r and omized trials . In addition , recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding . Therefore , a therapeutic window concept has been proposed for P2Y12 inhibitor therapy . In this up date d consensus document , we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events . In addition , we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy Despite multiple interventions to reduce the risk of cardiovascular disease , the majority of people with diabetes develop macrovascular complications , and mortality following myocardial infa rct ion remains unacceptably high [ 1 ] . Antiplatelet agents are used for both the primary and secondary prevention of cardiovascular disease , although current guidelines are not consistent in their recommendation for the use of aspirin in diabetes [ 2 ] . In fact , there is little direct evidence supporting its efficacy in this group of patients . Instead , there is convincing data in the literature to suggest inadequate cardiovascular protection by aspirin in diabetes . In a meta- analysis of 287 r and omised trials , antiplatelet treatment ( aspirin in most studies ) reduced the risk of ischaemic events by 22 % , but the risk reduction in the subgroup with diabetes was only 7 % , which was not statistically significant [ 3 ] . This outcome was mirrored in the Primary Prevention Project trial , which reported that cardiovascular risk reduction with aspirin was marginal and non-significant in the presence of diabetes [ 4 ] . Despite this , there are no published studies specifically design ed to evaluate the clinical efficacy of aspirin in individuals with diabetes , a surprising omission in the era of ‘ evidence based ’ medicine . These findings from clinical trials raise the question as to why there should be a reduction in the clinical efficacy of  aspirin  in patients with diabetes compared with a nondiabetic population . Diabetes is intrinsically associated with particular biochemical abnormalities that may have the capacity to diminish the effects of aspirin on platelet function and cardiovascular risk — a possibility that has led to the hotly debated concept of aspirin resistance [ 5 , 6 ] . Unfortunately , aspirin resistance suffers from a lack of a st and ardised definition , although now generally thought of as either ( 1 ) reflecting clinical aspirin resistance ( or perhaps , more accurately , treatment failure ) , characterised by the occurrence of a thrombotic episode despite treatment with aspirin ; or ( 2 ) biochemical aspirin resistance where platelet responses persist despite platelet exposure to aspirin . Controversy remains as to the cause of biochemical aspirin resistance , its relevance to clinical outcomes , and the place of aspirin treatment in the management of cardiovascular risk in diabetes patients . All of this highlights the urgent need to underst and the mechanisms that underpin the interactions between diabetes and aspirin , to establish the role of aspirin in particular , and antiplatelet therapy in general , in the amelioration of cardiovascular events in individuals with diabetes . Diabetologia ( 2008 ) 51:385–390 DOI 10.1007/s00125 - 007 - 0898 - 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 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 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 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 Aim While regular use of low-dose aspirin has been recommended for several groups of patients at risk of vascular occlusion , the optimal dose of aspirin to produce a cardiovascular benefit whilst minimizing side effects is uncertain . Further , while enteric coated preparations may reduce gastrointestinal symptoms , the antiplatelet effects of these formulations have not been completely tested . In addition , exceptionally few data relating to these issues have been available in women . Methods To determine whether a 100 mg alternate day dose of aspirin given in regular and enteric coated formulations for a 2-week period is sufficient to inhibit platelet function in men and women , a r and omized , double-blind , placebo-controlled trial was conducted among 22 healthy volunteers evaluating the effects of these preparations on platelet aggregation induced by arachidonic acid , adenosine diphosphate , and epinephrine , and on plasma concentrations of thromboxane and prostacyclin . Results During the active aspirin phase of the study , all subjects demonstrated a clinical anti-platelet effect as evidence d by failure of the platelets to aggregate in the presence of at least one platelet agonist , and mean thromboxane and prostacyclin levels decreased to 7.5 and 15.6 % of baseline , respectively ( both P < 0.001 ) . After cessation of active aspirin , all subjects had full recovery of platelet function as well as thromboxane and prostacyclin production . There were virtually no differences between regular and enteric coated formulations , or between men and women . Conclusion These data indicate that an alternate day regimen of 100 mg aspirin given in either regular or enteric coated formulation is adequate to achieve functional platelet inhibition . The clinical efficacy of this dose and formulation of aspirin is being tested in the ongoing Women 's Health Study , a r and omized , double-blind , placebo-controlled trial of 40 000 female health professionals design ed in part to assess the benefits and risks of 100 mg alternate day aspirin in the primary prevention of cardiovascular disease 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 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 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 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 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 Context The optimal aspirin dose for prevention of cardiovascular events is unknown . Contribution This post hoc analysis of CHARISMA trial data suggests no overall differences in efficacy or safety by aspirin dose . However , in the subgroup of patients r and omly assigned to clopidogrel , there was a hint of reduced efficacy and increased harm with higher doses . Caution Patients were not r and omly assigned to aspirin dose . Implication Lower aspirin doses ( 75 to 81 mg/d ) may optimize efficacy and safety for patients requiring aspirin for long-term prevention , especially those taking clopidogrel .  The Editors Aspirin is the most widely used drug worldwide for the prevention of thrombotic cardiovascular events . Of note , the doses of aspirin used most often clinical ly or recommended in guidelines are based not on the results of trials design ed to identify the most efficacious or safest dose , but on a combination of historical precedents and trials in which specific doses of aspirin were m and ated by protocol . This practice has led to a wide range in aspirin doses ( 75 to 325 mg/d ) recommended by the U.S. Food and Drug Administration ( 1 ) for the management of cardiovascular disease in various population s. Although as little as 30 mg of aspirin daily is needed to fully inhibit platelet thromboxane production ( 2 ) , doses more than 10 times higher than this are routinely used in long-term prevention of cardiovascular disease . Because aspirin has been used clinical ly for more than a century and is a mainstay of therapy for patients who have or are at risk for atherosclerotic disease and other common ailments , its risks are often underappreciated . However , given that more than one third of U.S. adults are estimated to take aspirin daily for cardiovascular disease ( 3 ) , even a very small incidence of hemorrhagic complications places a large number of people at risk . Consistent with this is a recent analysis of hospitalizations for adverse drug effects that found aspirin to be one of the most common causal agents ( 4 ) . The gastrointestinal tract is the leading source of bleeding events in  aspirin-treated  patients because of inhibition of gastroprotective prostacyclins , with an excess risk for upper gastrointestinal complications of 5 cases per 1000 aspirin users per year ( 5 ) . Prospect i ve evaluation of  aspirin-treated patients with coronary artery disease identified an incidence of upper gastrointestinal bleeding of 1.5 % per year , with substantial associated morbidity ( 6 ) . Because inhibition of gastric prostacyclin is dose-dependent and not maximal until a daily dose of about 1300 mg is reached ( 4 ) , minimizing the dose of aspirin to that needed to fully inhibit platelet thromboxane production would probably offer the greatest potential benefit with the lowest possible risk . In several observational studies of large prospect i ve trials , lower doses of aspirin ( < 162 mg/d ) have been associated with the lowest incidence of thrombotic events ( 7 , 8) and a trend toward fewer bleeding events ( 8) . These favorable trends in efficacy and safety were confirmed in the CURE ( Clopidogrel in Unstable angina to prevent Recurrent Events ) trial ( 9 ) of dual antiplatelet therapy with clopidogrel plus aspirin versus placebo plus aspirin . On the basis of these results , the design of the CHARISMA ( Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ) trial ( 10 ) , which r and omly assigned 15603 patients at high risk for atherothrombotic events to clopidogrel or placebo in conjunction with aspirin , m and ated a daily aspirin dose of 75 to 162 mg . We performed a post hoc analysis of associations between investigator-determined daily aspirin dose and thrombotic and hemorrhagic outcomes in the prospect i ve CHARISMA trial . Methods The design , methods , and primary results of the CHARISMA study are reported elsewhere ( 10 ) . In brief , CHARISMA was a multicenter , double-blind , r and omized , placebo-controlled trial of long-term clopidogrel ( 75 mg/d ) treatment versus placebo in patients 45 years or older who had established atherosclerotic disease or were asymptomatic but at high risk because of a combination of risk factors . All patients also received low-dose aspirin therapy , which was limited by protocol to between 75 and 162 mg/d . Patients were excluded if they had an established indication for clopidogrel therapy , such as a recent acute coronary syndrome or stent implantation . Clinical follow-up was done at 1 , 3 , and 6 months and every 6 months thereafter until the end of the trial . The actual dose of aspirin being taken was confirmed at each evaluation . The ethics committee at each of the 768 participating hospitals worldwide , as well as the appropriate national ethics committee for each of the 32 participating countries , review ed and approved the study protocol . All patients provided written informed consent before enrollment . The primary efficacy end point was the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . The primary safety end point was severe or life-threatening bleeding according to the GUSTO-I ( Global Utilization of Streptokinase and TPA for Occluded coronary arteries ) criteria ( 11 ) : intracerebral bleeding or bleeding result ing in substantial hemodynamic compromise requiring treatment . A secondary safety end point was the combined incidence of severe or life-threatening bleeding or moderate bleeding by the GUSTO-I criteria , with moderate defined as bleeding requiring transfusion but not result ing in hemodynamic compromise ( 11 ) . Of note , patients believed to be at high risk for bleeding were excluded from enrollment .  Aspirin dose was not r and omized ; rather , it was selected at the discretion of the treating physician . We prospect ively divided patients into 3 major groups according to clear demarcations in aspirin dose at baseline : less than 100 mg/d , represented almost entirely by doses of either 75 or 81 mg/d ; 100 mg/d ; and greater than 100 mg/d , represented by either 150 or 162 mg/d . We evaluated the relative efficacy and safety of the different doses of aspirin among all patients , and we evaluated the efficacy and safety end points between the treatment ( clopidogrel ) versus placebo groups by aspirin dose category . Statistical Analysis We performed all data analyses on the intention-to-treat population . We performed hypothesis tests by using 2-sided tests at the 5 % significance level . Baseline characteristics were compared by using chi-square tests for discrete variables and t tests for continuous variables . We calculated cumulative KaplanMeier estimates of the event rates and assessed differences in the unadjusted rates of primary efficacy and safety end points across the aspirin groups by using a 2-sided log-rank test . We used log-rank weights to compute a test for trend across aspirin dose categories . We estimated the treatment effect , measured by the hazard ratio and its 95 % CI , by using the Cox proportional hazards model . Multivariable modeling was performed to determine whether aspirin dose was independently associated with the primary efficacy and safety outcomes after controlling for potentially confounding factors . Because patients could have had more than 1 efficacy or safety event , we defined the time to the primary efficacy end point as the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . We defined the time to the primary safety end point as the first occurrence of severe or life-threatening bleeding according to the GUSTO-I criteria ( 11 ) . We selected variables for inclusion in the models on the basis of differences in baseline characteristics among patients in the 3 aspirin dose categories or their clinical relevance to the outcomes . Covariates included in the multivariable model for the primary efficacy end point were the continuous variables of age , weight , and systolic blood pressure and the categorical variables of sex ; race or ethnicity ( white or Hispanic vs. other ) ; hypertension ; hypercholesterolemia ; history of congestive heart failure ; previous myocardial infa rct ion ; previous stroke ; previous transient ischemic attack ; diabetes mellitus ; atrial fibrillation ; peripheral arterial disease ; diabetic nephropathy ; current smoking ; primary ( vs. secondary ) prevention and past use of statins , nitrates , and antiplatelet agents other than aspirin . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by aspirin dose category . Adjustment variables in the multivariable model for the primary safety end point ( GUSTO-I severe or life-threatening bleeding ) included age and weight as continuous variables and the categorical variables of stable angina with multivessel disease , sex , race or ethnicity ( white or Hispanic vs. other ) , history of congestive heart failure , previous myocardial infa rct ion , previous stroke , previous transient ischemic attack , diabetes mellitus , atrial fibrillation , peripheral arterial disease , diabetic nephropathy , hypertension , hypercholesterolemia , primary prevention ( vs. secondary ) , and current smoking . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by daily aspirin dose category . To adjust for geographical region without estimating its effect , we used region ( categorized as United States , Canada , Western Europe , Eastern Europe , Latin America , Asia and Australia , or Africa ) as a stratification variable in models for both end points . We assessed the interaction of  aspirin dose and r and omized treatment in both models . We calculated and tested the difference between the maximum likelihood ratios with and without 2 interaction terms ( r and omized treatment assignment by daily aspirin dose of 100 mg and greater than 100 mg ) . We assessed proportional hazards by multiplying each covariate by the log of the time to the event . A Wald test was performed to test the linear hypotheses of the regression coefficients . The proportional 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 Several case reports have implicated Ginkgo biloba in clinical ly adverse bleeding disorders .  Ginkgo biloba has been reported to increase pain-free walking distance among patients with peripheral artery disease ( PAD ) . St and ard PAD therapy includes 325 mg/day aspirin . The objective of this study was to examine potential adverse effects of concomitant aspirin and Ginkgo biloba on platelet function . Ginkgo biloba ( EGb 761 , 300 mg/day ) was compared with placebo for effects on measures of platelet aggregation among adults consuming 325 mg/day aspirin  in a r and omized , double-blind , placebo-controlled , parallel design trial of 4-week duration . Participants were adults , age 69 ± 10 years , with PAD or risk factors for cardiovascular disease . Outcome measures included platelet function analysis ( PFA-100 analyzer ) using ADP as an agonist ( n = 26 placebo ; n = 29 ginkgo ) , and platelet aggregation using ADP , epinephrine , collagen and ristocetin as agonists ( n = 21 placebo ; n = 23 ginkgo ) . Participants kept daily logs of bleeding or bruising episodes . There were no clinical ly or statistically significant differences between treatment groups for any agonists , for either PFA-100 analysis or platelet aggregation . Reports of bleeding or bruising were infrequent and similar for both study groups . In conclusion , in older adults with PAD or cardiovascular disease risk , a relatively high dose of Ginkgo biloba combined with 325 mg/day daily aspirin did not have a clinical ly or statistically detectable impact on indices of coagulation examined over 4 weeks , compared with the effect of aspirin alone . No adverse bleeding events were observed , although the trial was limited to a small sample size BACKGROUND Acetylsalicylic acid , or aspirin , is widely used in secondary prevention of coronary artery diseases , but the inhibition of platelet aggregation is not uniform in all individuals . OBJECTIVE To investigate the prevalence of aspirin resistance at rest and during exercise in coronary artery disease patients . MATERIAL S AND METHODS Fifty patients with stable coronary artery disease were prospect ively studied . All patients received aspirin ( 75 - 300 mg/day for > 1 month ) and no other antiplatelet therapy . Aspirin resistance was studied , at rest and immediately after a stress test , using the st and ardized platelet function analyzer ( PFA-100(R ) , Dade-Behring ) . Aspirin resistance was defined as a normal collagen/epinephrine closure time ( < 186 s ) . RESULTS Ten patients ( 20 % ) were  aspirin-resistant  at rest . Out of the 40 patients who were aspirin-sensitive at rest , 9 ( 22 % ) were aspirin-resistant immediately after the exercise stress test . There were no differences in aspirin sensitivity regarding gender , age , diabetes , hypertension , dyslipidemia , platelet count , medical treatment or number of the coronary arteries involved . CONCLUSIONS Aspirin resistance is detected , at rest , in 20 % of our patients with stable coronary artery disease .  Aspirin treatment does not seem to protect against exercise-induced platelet activation in 22 % of such patients , despite aspirin sensitivity at rest Context National guidelines recommend aspirin or statin drugs individually to reduce first coronary heart disease ( CHD )  events , but there are no guidelines about taking both . Contribution The authors used a Markov model to estimate the cost-effectiveness of aspirin , statins , both drugs , or neither in men . In patients with a 10-year risk for CHD of 7.5 % , aspirin alone reduced costs and lengthened life compared with no treatment . Adding a statin cost $ 56200 per additional quality -adjusted life-year at a 7.5 % risk but only $ 42500 at a 10 % risk . Caution s The authors ' analysis was limited to men . Implication s Therapy with aspirin alone is effective and cost-effective in men with an average level of risk for CHD . The addition of a statin is more cost-effective as risk increases . The Editors Aspirin and statin drugs have been shown to be effective for preventing first coronary heart disease ( CHD ) events ( 1 - 3 ) . Systematic review s and meta-analyses suggest that the relative risk reductions with both forms of therapy are similar in magnitude and seem to be independent and relatively constant across the range of underlying risk for CHD ( 2 - 5 ) . The absolute benefit from these treatments seems to be proportional to the patient 's underlying risk for CHD . National treatment guidelines recommend aspirin and statin drugs individually for the primary prevention of cardiovascular events in men who are at increased risk ( 4 , 6 , 7 ) . However , no U.S. guidelines have addressed how these drugs should be used together , and we are unaware of any previous analyses that have reported the cost-effectiveness of these drugs when used in combination for CHD prevention . To help inform clinical and policy decisions about primary CHD prevention , we performed a costutility analysis that examined the use of aspirin therapy , statin therapy , or combination therapy with both drugs in men with various underlying levels of risk for CHD . Methods To examine the cost and utility associated with aspirin and with statin use , we used Microsoft Excel 2002 for Windows ( Microsoft Corp. , Redmond , Washington ) to develop a Markov state-transition model . The model was design ed to simulate cohorts of initially healthy middle-aged men with no history of cardiovascular events and with various levels of 10-year risk for CHD ( Figure 1 ) . Figure 1 . General structure of the Markov model . Base-Case Scenario In our base-case scenario , we compared the effectiveness of 10 years of aspirin therapy , statin therapy , combination therapy with both drugs , and no therapy in 45-year-old men with a 10-year risk for CHD of 7.5 % . After 10 years , both groups adopted the treatment used in the intervention group . Although the differences in therapy were maintained for only 10 years , we examined the effects of these therapies over a lifetime . Model Assumptions All persons were initially healthy and progressed through the model in annual cycles . In each cycle , an individual remained healthy , had an initial cardiovascular event ( angina , myocardial infa rct ion , or stroke ) , experienced adverse effects from therapy ( gastrointestinal bleeding from aspirin or myopathy from statins ) , or died . We assumed that those who had cardiovascular events or adverse events stayed in the subacute state for the remainder of that cycle and then entered a postevent state . Adherence to treatment was assumed to be 100 % in the absence of adverse effects , although the treatment efficacy data were based on the actual rates of adherence in the clinical trials . Persons who had adverse effects from therapy stopped taking the offending medication ; their procession through the model was similar to that of healthy patients after the initial cycle . All costs and outcomes were discounted at 3 % in accordance with current consensus recommendations ( 8) . Model Parameters Model parameters , including base-case values , ranges , and references , are shown in Table 1 ( 1 - 3 , 9 - 29 ) . Table 1 . Base-Case Estimates and Ranges Used in Sensitivity Analyses Noncardiovascular Mortality Age-dependent noncardiovascular mortality rates were estimated from the National Vital Statistics life tables ( 31 ) . Rates were adjusted as the cohort aged over the time horizon of the analysis . Cardiovascular Event Rates Baseline risks for initial cardiovascular events ( myocardial infa rct ion , stroke , angina , and death from CHD ) were drawn from Framingham risk equations by using hypothetical scenarios of nonsmoking , nonhypertensive , nondiabetic men at different levels of risk for CHD ( Appendix Table ) ( 32 ) . Assuming an exponential distribution , we translated these 10-year risks into annual event-related transition probabilities . These probabilities were allowed to change over time to reflect increasing risk for CHD over the time horizon of the analysis . Appendix Table . Sample Baseline Characteristics of 45-Year-Old Men by Risk Level Because we were interested in primary prevention , we did not simulate or examine the details of a patient 's course after a primary , nonfatal event . Instead , we assigned them an increased risk for death , increased costs , and decreased utilities by using data from the literature regarding the average experience of patients after an initial event . The increased relative risk for death after an initial event ( Table 1 ) was drawn from population -based studies in the United Kingdom ( 12 , 16 ) and applied to the general mortality rates from the U.S. life tables to generate the estimated postevent mortality rates . We modified these event rates by assuming that all patients received optimal secondary prevention . Adverse Effects The excess risks for gastrointestinal bleeding with aspirin use and for myopathy with statin use were drawn from systematic review s of r and omized trials and a recent secondary data analysis ( 2 , 26 , 27 ) . Risks for gastrointestinal bleeding and myopathy in untreated patients were assumed to be zero so that only treatment-induced adverse events were counted . Because better data were not available , we estimated the risks for death from aspirin-related gastrointestinal bleeding and statin-induced myopathy and varied them in sensitivity analysis . Patients who had nonfatal adverse effects were not given therapy with alternate agents for primary prevention of CHD . Modeling Stroke Because many r and omized trials of aspirin prophylaxis did not distinguish by stroke type , we had difficulty estimating the precise effect of aspirin on ischemic and hemorrhagic strokes ( 30 ) . To account for this limitation , we used 2 approaches to model the effect of aspirin on stroke . In the base-case analysis , we followed the approach that was used in a recent meta- analysis ( 9 ) by including hemorrhagic stroke and ischemic stroke together in 1 estimate of the effect of aspirin on total stroke ( relative risk for stroke with aspirin , 1.06 ) . In an alternate scenario , we modeled hemorrhagic stroke and ischemic stroke as separate health states . We assumed that aspirin was associated with an excess annual risk of 20 hemorrhagic strokes per 100000 users on the basis of published meta-analyses and that one third of these hemorrhagic strokes would be fatal ( 19 , 30 , 33 ) . We conservatively assumed that aspirin had no effect on ischemic stroke ( 30 ) . The costs and utilities of ischemic stroke and hemorrhagic stroke were also considered separately . Treatment Efficacy We used summary relative risk estimates from existing meta-analyses or relative risks from individual trials to estimate the efficacy of aspirin and statin therapy , either alone or in combination , for preventing CHD events ( 3 , 24 , 29 ) . Where data were limited , we made conservative assumptions . The efficacy of the combined use of aspirin and statins was assumed to be independent on the basis of data from secondary prevention trials ( 5 ) . We did not model the effect of aspirin or statins on initial use of revascularization procedures in the absence of a cardiovascular event . All patients who survived an initial cardiovascular event were assumed to have received secondary preventive therapy with aspirin and a statin or with an alternate agent if  they could not tolerate  aspirin  or  statins . The effect of treatments on all-cause mortality was estimated from meta-analyses of secondary prevention trials ( 18 - 20 ) . Costs We conducted our analysis from the perspective of a third-party payer . State costs ( Table 1 ) , which were derived from data from the published literature and several recent national data bases , are expressed in 2003 dollars . To estimate the costs during the year in which an event occurred , we estimated acute care costs by drawing on data regarding hospital charges from the Healthcare Utilization Project data base and by converting these values to costs . To convert hospital charges to costs , we used the 1999 cost-to-charge ratio value of 0.4501 , which was derived from the Medicare Provider Analysis and Review of short-stay hospitals ( 28 ) . We then used the Medical Consumer Price Index to generate an inflation factor of 1.195 , which was applied to the 1999 cost figure to convert 1999 dollars to 2003 dollars ( 17 ) . In addition to the acute care costs , we assumed that each patient who survived an acute event would also incur one half of the estimated ongoing annual costs of care for the first year . Costs for subsequent years were based on ongoing costs of care that were drawn from the medical literature ( 22 - 25 ) . Drug costs were obtained from the 2003 Red Book average wholesale prices ( 21 ) . For our base-case analysis , we set the annual  statin cost to $ 730 by averaging the Red Book prices of simvastatin ( $ 922 for 10 mg/d ) and lovastatin ( $ 503 for 10 mg/d ) . The base-case cost of aspirin was based on an annual cost of $ 16 for Bayer aspirin ( Bayer Healthcare LLC , Morristown , New Jersey ) . The annual cost of generic aspirin  was estimated at approximately $ 6 ( 21 ) . We varied the costs of each drug over wide ranges in sensitivity analysis . To check our cost estimates , we compared our derived values with other cost estimates Aspirin , compared with placebo , reduces the risk of cardiovascular events by 25 % in population s of patients with and without known arterial vascular disease . However , the phenomena of ‘ aspirin resistance ’ that has been described in 5–50 % of this population may critically reduce aspirin 's efficacy . One study has suggested that aspirin-resistant patients have a 3.5 times higher risk of cardiovascular death . Presently , there are no established , simple , broadly used methods determining antiplatelet properties of aspirin , while conventional aggregometry requires special equipment and trained personnel . We sought to determine the validity of an Ultegra analyzer with the novel aspirin-sensitive cartridge before and after one pill of non-enteric coated aspirin ( 325 mg ) in subjects with multiple risk factors for coronary artery disease . One hundred and fifty-four volunteers were enrolled into the multicenter study , but six of them were excluded . Data from 148 participants were analyzed . Platelets were assessed twice at baseline ( pre-aspirin ) , and after 2–30 h ( post-aspirin ) . We employed 5 μmol/l epinephrine-induced conventional aggregometry , and aspirin response units stimulated by propyl gallate with the point-of-care Ultegra analyzer . A single pill of aspirin  reduced platelet-rich plasma aggregation from 72 ± 21 % to 25 ± 10 % , and diminished aspirin reduction units from 647 ± 95 to 436 ± 69 . The overall agreement between the two methods was 87 % with 85 % sensitivity for Ultegra and 88 % for platelet aggregation , respectively . The correlation between the two methods was 0.902 . Timely determination of aspirin resistance represents an indispensable application in current medicine . The Ultegra RPFA-ASA analyzer is a novel , fast method that could be used in clinical practice for monitoring efficacy of aspirin , and for triaging the aspirin-resistant population . The clinical implication s of these data need to be proven in r and omized trials 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 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 OBJECTIVE We aim ed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin ; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin . METHODS We performed a r and omized , double-blind , placebo-controlled , crossover trial , comparing clopidogrel 75 mg day(-1 ) versus placebo , in 36 aspirin-treated patients with symptomatic objective ly confirmed peripheral arterial disease . RESULTS The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid , urinary 11 dehydro thromboxane B2 concentrations , or soluble markers of platelet activation markers ( P-selectin , CD40-lig and ) and inflammation ( high sensitivity serum C-reactive protein , interleukin-6 ) . Clopidogrel significantly inhibited platelet aggregation induced by ADP ( reduction 26.2 % ; 95 % CI : 21.3 - 31.1 % , P < 0.0001 ) and collagen ( reduction 6.2 % ; 95 % CI : 3.2 - 9.3 % , P = 0.0003 ) . The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [ lower tertile of arachidonic acid-induced platelet aggregation : 2.8 % ( 95 % CI : -0.8 to 6.3 % ) reduction in mean collagen-induced aggregation by clopidogrel ; middle tertile : 4.0 % ( 95 % CI : 0.4 - 7.6 % ) ; upper tertile 12.6 % ( 95 % CI : 4.5 - 20.8 % ) ; P-value for interaction 0.01 ] . CONCLUSIONS The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin . This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin . Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor , thereby overcoming the problem of laboratory aspirin resistance 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 Background — Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients , and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events , especially after coronary angioplasty . Whether this reflects suboptimal platelet inhibition per se , which might benefit from more potent antiplatelet agents such as tirofiban , is unknown . Methods and Results — We screened 1277 patients to enroll 93 aspirin , 147 clopidogrel , and 23 dual poor responders , based on a point-of-care assay , who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease . Patients were r and omly assigned in a double-blind manner to receive either tirofiban ( n=132 ) or placebo ( n=131 ) on top of st and ard aspirin and clopidogrel therapy . The primary end point , consisting of troponin I/T elevation at least 3 times the upper limit of normal , was attained in 20.4 % ( n=27 ) in the tirofiban group compared with 35.1 % ( n=46 ) in the placebo group ( relative risk , 0.58 ; 95 % confidence interval , 0.39 to 0.88 ; P=0.009 ) . The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced ( 3.8 % versus 10.7 % ; P=0.031 ) . The overall incidence of bleeding was low , likely explained by a substantial use of the transradial approach , and did not differ between the 2 groups . Conclusions — In low-risk patients according to clinical presentation who had poor responsiveness to st and ard oral platelet inhibitors via a point-of-care assay , intensified platelet inhibition with tirofiban lowers the incidence of myocardial infa rct ion after elective coronary intervention 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 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 Aspirin prevents the production of thromboxane A2 ( TXA2 ) by irreversibly inhibiting platelet cyclooxygenase , exhibiting antiplatelet actions . This agent has been reported to prevent relapse in patients with ischemic heart disease or cerebral infa rct ion via this action mechanism . However , there are individual differences in this action , and aspirin is not effective in some patients , which is referred to as ‘ aspirin resistance ’ . In this study , we analyzed laboratory aspirin resistance by platelet aggregation in 110 healthy adult Japanese males using 24 single-nucleotide polymorphisms ( SNPs ) of nine genes involved in platelet aggregation/hemorrhage . Among SNPs involved in platelet aggregation , aspirin  was less effective for 924 T homozygote of a TXA2 receptor , 924T > C , and 1018C homozygote of a platelet membrane glycoprotein GPIbα , 1018C > T , suggesting that 924 T and 1018C alleles are involved in aspirin resistance BACKGROUND Aspirin and clopidogrel resistance plays a significant role in the development of cardiovascular ischemic events for ninety patients undergoing percutaneous coronary intervention . Recent studies have indicated that increasing the dose of antiplatelet drugs maybe a potent method to improve the inhibition of platelet aggregation . METHODS  Thrombelastograph ( TEG ) determinations were used to evaluate the effect of antiplatelet therapy . According to the results , 90 patients were divided into three groups and given different doses of aspirin and clopidogrel . Thirty patients with both an inhibition rate of  aspirin > 50 % and an inhibition rate of clopidogrel > 50 % were defined as the control group . Sixty patients with an inhibition rate for aspirin < 50 % and an inhibition rate for clopidogrel < 50 % were defined as the resistance group . Patients in resistance group were r and omly assigned to be given a routine dose ( 100 mg aspirin plus 75 mg clopidogrel per day , which we called a resistance plus routine dose group , R + R ) and a loading dose ( 200 mg aspirin and 150 mg clopidogrel per day , which we called resistance plus loading dose group , R + L ) of antiplatelet therapy . A 12-month follow-up was observed to examine the change of inhibition rate of antiplatelet therapy and to estimate the relationship between inhibition rate and the occurrence of cardiovascular ischemic events . RESULTS After 6 months of antiplatelet therapy , the inhibition rate of aspirin  in the R + L group increased from ( 31.4 ± 3.7)% to ( 68.6 ± 7.1)% , which was significantly higher than that in R + R group , ( 51.9 ± 8.2)% ( P < 0.01 ) . The inhibition rate of clopidogrel  in the R + L group increased from ( 22.1 ± 3.8)% to ( 60.2 ± 7.4)% , which was significantly higher than in the R + R group , ( 45.9 ± 4.3)% ( P < 0.01 ) . The occurrence rates of cardiovascular ischemic events , stent thrombosis , recurrent unstable angina and myocardial infa rct ion in the R + R group were 20 % , 36 % and 17 % , respectively . Occurrence was significantly increased compared with that in the control group , 3 % , 10 % and 1 % , respectively ( P < 0.01 ) . In contrast , the occurrence rates in the R + L group ( 10 % , 23 % and 6 % , respectively ) were attenuated compared with those in the R + R group ( P < 0.01 ) , although still higher than in the control group ( P < 0.01 ) . CONCLUSIONS Almost all of the cardiovascular ischemic events occurred in the first six months after percutaneous coronary intervention . According to the result of TEG determinations , earlier application of a loading dose of aspirin and clopidogrel can decrease the rate of recurrent cardiovascular ischemic events Background —Aspirin is widely used as an antiplatelet drug in patients with coronary heart disease . Despite documented clinical benefit , many patients on aspirin  still experience severe cardiovascular events . Several laboratory reports have shown lack of platelet inhibition in 5–40 % of aspirin‐treated patients , and the term aspirin resistance has been introduced . The clinical relevance of these laboratory findings is , however , still unknown . New antiplatelet drugs have been developed , and the adenosin diphosphate ( ADP ) receptor inhibitor clopidogrel has at least the same efficacy as aspirin with an acceptable safety profile . Laboratory methods for determination of platelet reactivity and treatment efficacy have been complicated and time consuming . New method ologies , like the PFA‐100 ® system , have made such analyses more suitable for clinical use . Design —In the ASCET study , 1000 patients with documented coronary heart disease will be r and omized to either continued treatment with aspirin 160 mg/d or change to clopidogrel 75 mg/d after initial determination of their platelet reactivity while on aspirin treatment . Clinical endpoints will be recorded for at least 2 years and related to the initial aspirin response We report the incidence of  aspirin  nonresponsiveness  in a prospect i ve , multicenter registry ( n=422 patients ) to be 23 % using the Ultegra Rapid Platelet Function Assay-ASA , and determined a history of coronary artery disease to be associated with twice the odds of being an  aspirin nonresponder ( odds ratio 2.01 , 95 % confidence interval 1.189 to 3.411 , p=0.009 ) . Further prospect i ve studies are needed to correlate  aspirin nonresponsiveness to adverse clinical events 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 Background Haemodialysis ( HD ) is critically dependent on the availability of adequate access to the systemic circulation , ideally via a native arteriovenous fistula ( AVF ) . The Primary failure rate of an AVF ranges between 20–54 % , due to thrombosis or failure of maturation . There remains limited evidence for the use of anti-platelet agents and uncertainty as to choice of agent(s ) for the prevention of AVF thrombosis . We present the study protocol for a r and omised , double-blind , placebo-controlled , clinical trial examining whether the use of the anti-platelet agents , aspirin and omega-3 fatty acids , either alone or in combination , will effectively reduce the risk of early thrombosis in de novo AVF . Methods / Design The study population is adult patients with stage IV or V chronic kidney disease ( CKD ) currently on HD or where HD is planned to start within 6 months in whom a planned upper or lower arm AVF is to be the primary HD access . Using a factorial- design trial , patients will be r and omised to aspirin or matching placebo , and also to omega-3 fatty acids or matching placebo , result ing in four treatment groups ( aspirin placebo/omega-3 fatty acid placebo , aspirin/omega-3 fatty acid placebo , aspirin placebo/omega-3 fatty acid , aspirin/omega-3 fatty acid ) . R and omisation will be achieved using a dynamic balancing method over the two stratification factors of study site and upper versus lower arm AVF . The medication will be commenced pre-operatively and continued for 3 months post surgery . The primary outcome is patency of the AVF at three months after r and omisation . Secondary outcome measures will include functional patency at six and twelve months , primary patency time , secondary ( assisted ) patency time , and adverse events , particularly bleeding . Discussion This multicentre Australian and New Zeal and study has been design ed to determine whether the outcome of surgery to create de novo AVF can be improved by the use of aspirin and /or omega-3 fatty acids . Recently a placebo-controlled trial has shown that clopidogrel is effective in safely preventing primary AVF thrombosis , but ineffective at increasing functional patency . Our study presents significant differences in the anti-platelet agents used , the study design , and surgical and patient demographics that should contribute further evidence regarding the efficacy of anti-platelet agents . Trial Registration Australia & New Zeal and Clinical Trials Register ( ACTRN12607000569404 ) 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 CONTEXT Recent r and omized trials suggest that women may not accrue the same cardioprotective benefits as men do from low-dose aspirin therapy used in primary prevention . Failure of aspirin to suppress platelet aggregation in women is one hypothesized mechanism . OBJECTIVE To examine differential platelet reactivity to low-dose aspirin therapy by sex . DESIGN , SETTING , AND PARTICIPANTS A clinical trial of aspirin at 81 mg/d for 14 days was conducted in 571 men and 711 women . Baseline and post-aspirin therapy measures included platelet aggregation to arachidonic acid , adenosine diphosphate , epinephrine , and platelet function analyzer closure time . MAIN OUTCOME MEASURE Sex differences in cyclooxygenase 1 ( COX-1 ) direct and indirect platelet activation pathways before and after administration of aspirin . RESULTS In 10 of the 12 platelet agonist exposures , women 's platelets were significantly more reactive at baseline . However , after aspirin therapy , the percent aggregation to arachidonic acid ( the direct COX-1 pathway ) decreased more in women than in men ( P<.001 ) and demonstrated near total suppression of residual platelet reactivity in both men and women . In COX-1 indirect pathways , women experienced the same or more platelet inhibition than men in 8 of the 9 assays yet retained modestly greater platelet reactivity after aspirin therapy . In multivariable analysis , female sex significantly predicted aggregation to 2 muM and 10 muM of adenosine diphosphate ( P = .02 and < .001 , respectively ) and collagen at 5 mug/mL ( P<.001 ) independent of risk factors , age , race , menopausal status , and hormone therapy . CONCLUSIONS Women experienced the same or greater decreases in platelet reactivity after aspirin therapy , retaining modestly more platelet reactivity compared with men . However , most women achieved total suppression of aggregation in the direct COX-1 pathway , the putative mechanism for aspirin 's cardioprotection BACKGROUND Aspirin ( acetylsalicylic acid ) irreversibly inhibits platelet cyclooxygenase (COX)-1 , the enzyme that converts arachidonic acid ( AA ) to the potent platelet agonist thromboxane ( TX ) A2 . Despite clear benefit from aspirin in patients with cardiovascular disease ( CAD ) , evidence of heterogeneity in the way individuals respond has given rise to the concept of ' aspirin resistance . ' AIMS To evaluate the hypothesis that incomplete suppression of platelet COX as a consequence of variation in the COX-1 gene may affect aspirin response and thus contribute to aspirin resistance . PATIENTS AND METHODS Aspirin response , determined by serum TXB2 levels and AA-induced platelet aggregation , was prospect ively studied in patients ( n = 144 ) with stable CAD taking aspirin ( 75 - 300 mg ) . Patients were genotyped for five single nucleotide polymorphisms in COX-1 [ A-842 G , C22 T ( R8W ) , G128A ( Q41Q ) , C644A ( G213 G ) and C714A ( L237 M ) ] . Haplotype frequencies and effect of haplotype on two platelet phenotypes were estimated by maximum likelihood . The four most common haplotypes were considered separately and less common haplotypes pooled . RESULTS COX-1 haplotype was significantly associated with aspirin response determined by AA-induced platelet aggregation ( P = 0.004 ; 4 d.f . ) . Serum TXB2 generation was also related to genotype ( P = 0.02 ; 4 d.f . ) . CONCLUSION Genetic variability in COX-1 appears to modulate both AA-induced platelet aggregation and thromboxane generation . Heterogeneity in the way patients respond to aspirin may in part reflect variation in COX-1 genotype The in vitro closure time ( CT ) , determined by the Platelet Function Analyzer ( PFA‐100TM ) , is used to monitor patients treated with aspirin . A relatively high percentage of in vitro aspirin resistance was reported despite an adequate inhibition of platelet response to arachidonic acid and we investigated whether high plasma levels of von Willebr and factor ristocetin cofactor activity ( vWF : RCo ) may contribute to this profile . Platelet aggregation test , CT [ collagen adrenaline ( CEPI‐CT ) and collagen adenosine 5′‐diphosphate ( ADP ) ( CADP‐CT ) ] , and vWF : RCo levels were evaluated in 55 consecutive patients receiving aspirin ( 75–250 mg/d ) versus 32 untreated control subjects . All the aspirin‐treated patients showed platelet aggregation responses that reflected the aspirin intake . However , CT data analysis enabled aspirin good‐responder ( GR ) and aspirin bad‐responder ( BR ) patients to be identified . All GR group subjects ( n = 27 ) , had a CEPI‐CT and a CADP‐CT longer than 300 s and 96 s respectively . The BR group ( n = 28 ) had CEPI‐CT values below 200 s and all CADP‐CT were in the normal range ( 77 ± 19 s ) . Interestingly , the BR plasma vWF : RCo levels were significantly higher ( 159 ± 43 % ) than those of the GR group ( 121 ± 34 % ) ( P < 0·01 ) , which were similar to control values ( 114 ± 31 % ) . A negative correlation between vWF : RCo and CT values was established . We demonstrate that in vitro  aspirin‐resistance , revealed by PFA‐100TM CT prolongation failure , is correlated to increased plasmatic vWF : RCo levels , reinforcing its particular importance in PFA‐100TM cartridges performance Colorectal cancer is the second leading cause of cancer-related death in the United States , with 129 400 new cases and 56 600 deaths estimated to have occurred in 1999 ( 1 ) . Most cases of colorectal cancer arise from adenomatous polyps ( 2 ) . Screening has been shown to decrease colorectal cancer incidence and mortality rates ( 3 , 4 ) , and various decision analyses support its cost-effectiveness ( 510 ) . Despite demonstrated clinical and economic benefits , however , use of screening tests is low ( 1113 ) . In a large population -based study , 19.8 % of respondents reported having fecal occult blood testing during the preceding year and 30.4 % reported having sigmoidoscopyproctoscopy during the preceding 5 years ; 9.5 % had had both tests ( 13 ) . In a national strategy to decrease the burden of colorectal cancer , aspirin chemoprevention is a potentially powerful adjunct to screening . Numerous casecontrol ( 1421 ) and cohort studies ( 2226 ) support the hypothesis that aspirin and other nonsteroidal anti-inflammatory drugs ( NSAIDs ) decrease the incidence of colorectal adenoma and colorectal cancer and the mortality rate from colorectal cancer by 30 % to 65 % . Many animal models show that NSAIDs have an antitumor effect in the colon ( 27 ) . However , the Physicians ' Health Study , a r and omized study of male physicians that was not design ed to examine colorectal cancer specifically , found no decrease in colorectal cancer incidence when 325 mg of aspirin on alternate days was compared with placebo ( 28 ) . These results may conflict because of the specific dose and duration used and the patients studied . Aspirin is of proven benefit in secondary prevention of cardiovascular morbidity and death ( 29 ) and in primary prevention of myocardial infa rct ion in men ( 30 ) . However , its use for primary cardiovascular prevention remains controversial , in part because mortality prevention is unproven and no r and omized studies in women exist ( 29 ) . Although it is well recognized that aspirin may cause major complications ( 3035 ) , prophylactic aspirin is prescribed on the basis of cardiovascular considerations . In contrast , aspirin is unlikely to be prescribed for colorectal cancer prevention until better estimates of its benefits and risks become available . Since such data are unlikely to be available for the general U.S. population in the near future , we constructed a decision analytic model to explore the incremental clinical and economic effects of aspirin when it is added to an accepted screening program for sporadic colorectal cancer . Accepted screening programs consisted of flexible sigmoidoscopy every 5 years and yearly  fecal occult blood testing ( FS/FOBT ) ( 8 , 36 ) or screening colonoscopy every 10 years ( COLO ) , an emerging alternative screening strategy ( 710 , 37 ) . Our primary aim was to clarify whether aspirin chemoprevention might prove to be a cost-effective adjunct to screening . In secondary analyses , we examined the potential role of aspirin chemoprevention in an unscreened population and the effects of screening when added to existing aspirin use . Methods Literature Review We search ed MEDLINE from 1980 to 1999 for English- language literature that provided data on colorectal cancer , screening , aspirin chemoprevention , and aspirin-related complications . Model inputs were based on the literature search and on rigorous literature review s by a multidisciplinary expert panel from the Agency for Health Care Policy and Research ( 8) and by the Office of Technology Assessment ( 7 ) ( Table 1 ) . Table 1 . Inputs in the Cost-Effectiveness Model Decision Analytic Model We created a Markov model using DATA 3.0 ( TreeAge Software Inc. , Williamstown , Massachusetts ) ; Excel 2000 ( Microsoft Corp. , Redmond , Washington ) was used for analysis . The Markov model estimated the clinical and economic consequences of six strategies : natural history ( no aspirin or screening ) , FS/FOBT , COLO , aspirin alone ( ASA ) , FS/FOBT and aspirin ( FS/FOBT/ASA ) , and colonoscopy and aspirin ( COLO/ASA ) . Beginning at 50 years of age , patients progressed through the model for 30 1-year cycles ; principal states were normal , polyp , cancer ( localized , regional , or distant ) , and dead . The Markov model is discussed in detail in the Appendix . To reflect the effect of aspirin in the general population and not in an individual , we varied the percentage of persons in the population who adhered to screening . Using population -based data ( 13 ) , we selected a screening adherence rate of 25 % to reflect current practice . The general population , men , and women were examined separately . Natural History of Sporadic Colorectal Cancer We constructed a model of the natural history of sporadic colorectal cancer in patients at average risk for the disease . Epidemiologic data on colorectal cancer were derived from the Surveillance , Epidemiology , and End Results ( SEER ) program ( 38 ) . According to results of autopsy studies , adenomatous polyp prevalence was assumed to increase from 15 % at 50 years of age to 47 % at 75 years of age ( 16 % to 54 % in men ; 15 % to 40 % in women ) ( 3941 ) . We assumed that 90 % of tumors develop from polyps and that cancer progresses from localized to regional ( 2 years in each state ) to disseminated , with symptomatic presentation by stage as reflected in SEER data . Age-specific transition probabilities were calculated between normal , polyp , and cancer to yield polyp and cancer rates derived from the literature . Age-specific noncolorectal cancer mortality rates were derived from U.S. life tables ( 46 ) . Effect of Colorectal Cancer Screening We selected FS/FOBT as an accepted strategy endorsed by published guidelines ( 8 , 36 ) . In the model , any positive test result was followed by colonoscopy and , if necessary , polypectomy . If the results of colonoscopy were normal , screening resumed in 10 years . After an adenoma was detected , surveillance colonoscopy was performed every 5 years . Although specific patients with high-risk or low-risk adenomas may undergo surveillance at different intervals , we chose 5 years to reflect the average surveillance interval for the population . Colonoscopy was performed at cancer diagnosis and 3 years and every 5 years thereafter ( 8) . As long as results of screening tests remained negative , FS/FOBT was continued . Emerging data from clinical studies and decision analyses suggest that colonoscopy is a cost-effective screening tool ( 710 , 37 ) . Therefore , COLO was examined as an alternative screening strategy . In the model , colonoscopy was performed every 10 years as long as no adenoma or cancer was detected . Surveillance after adenoma detection was the same as that described for FS/FOBT . Effect of Aspirin Aspirin , 325 mg/d , was added to the screening and natural history strategies . In the base case , aspirin was estimated to reduce colorectal cancer risk by 30 % through equal reductions in adenoma incidence and progression to cancer ( 1426 ) . Aspirin may increase occult gastrointestinal blood loss ( 4753 ) , which could affect the FS/FOBT strategy . In the base case , we assumed that aspirin did not affect fecal occult blood testing because increases in blood loss have been reported only with high doses ( 4853 ) and low doses have been reported to have no effect on fecal occult blood testing ( 5456 ) . The protective effect of NSAIDs is not explained by earlier detection of adenomas or cancer ( 19 , 26 ) ; however , increased sensitivity and decreased specificity of FS/FOBT in patients receiving aspirin were assessed in the sensitivity analysis . In the model , aspirin-related complications were followed by aspirin withdrawal and return to baseline risk for colorectal cancer . Using data from trials of low-dose aspirin , we calculated rates of excess serious complications in patients taking aspirin . The rates were 1.4 per 10 000 person-years in patients younger than 65 years of age and 28 to 40 per 10 000 person-years in older patients with cerebrovascular disease ( 30 , 3234 ) . The 1-year prevalence of serious gastrointestinal NSAID-related complications is estimated to increase eightfold after 65 years of age ( 31 ) . Thus , we selected a base-case rate of 2 per 10 000 person-years before 65 years of age and 16 per 10 000 person-years thereafter for serious aspirin-related complications . We modeled mortality rates of 2 % to 8 % after a serious aspirin-related complication ( 4244 ) . We did not include changes in cardiovascular outcomes in the base case for several reasons . First , the role of aspirin in primary cardiovascular prevention is controversial , largely because prevention of death is unproven ( 29 ) . A recent decision analysis suggested that aspirin may be harmful in cohorts at low risk for cardiovascular events and may be only minimally beneficial as risk increases ( 57 ) . Second , aspirin may increase the incidence of hemorrhagic stroke ( 30 ) , and the balance of risks and benefits is unknown , particularly in women ( 29 ) . Third , in patients with cardiovascular indications for aspirin  , a potential effect on colon cancer is unlikely to affect prescribing decisions . Thus , we chose to examine the incremental benefit of colorectal cancer screening in a population already receiving aspirin . In the sensitivity analysis , we examined the effect of aspirin by assuming that it reduced cardiovascular mortality . Cardiovascular death accounts for 30 % to 42 % of deaths , depending on age ( 46 ) . Costs Procedure costs were derived from Medicare fee schedules and include professional fees and median procedure reimbursement . We used the wholesale cost of aspirin at the University of Michigan pharmacy , Ann Arbor , Michigan . Complication costs were derived from relevant diagnostic related groups ( 45 ) . Costs for care of stage-specific colon cancer were taken from reports to the National Cancer Institute ( 7 ) . All costs are in 1998 U.S. dollars ( Table 1 ) . Outcomes Colorectal cancer cases by stage , deaths by cause , average life-years after age 50 years , total costs , and itemized costs were determined for each strategy . Costs and life-years were 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 BACKGROUND Aspirin has a significant effect on hemostasis , so it is often recommended that patients taking aspirin  discontinue treatment before elective surgery . While off aspirin , these patients may be at risk of thrombosis . The optimum period of time that aspirin should be withheld is controversial . The aim of this study was to establish the duration of the antihemostatic effect of prolonged aspirin therapy . STUDY DESIGN In a prospect i ve study , 51 healthy volunteers were r and omly assigned into 3 groups , each receiving an identical tablet for 14 days . One group received a placebo tablet ; individuals in the other two groups received either 75 mg or 300 mg of aspirin once a day .  Template bleeding times and specific platelet function testing ( using the PFA-100 ; Dade Behring ) were carried out on subjects before therapy and again after its completion until they returned to baseline . RESULTS Thirty-eight volunteers complied sufficiently with the protocol to provide useful results . All bleeding times normalized within 96 hours and all platelet function tests within 144 hours after stopping aspirin . There was no demonstrable hemostatic defect in any volunteer persisting by or beyond the sixth day after treatment cessation . There was no apparent difference in duration of effect between those taking either 75 mg or 300 mg of aspirin . CONCLUSIONS This study uses sensitive measures of platelet function to demonstrate the duration of increased bleeding tendency after withdrawal of aspirin therapy . It supports discontinuation of aspirin therapy 5 days before elective surgery ( with the operation being performed on the sixth day ) BACKGROUND Aspirin is a frequently prescribed drug for primary and secondary prevention of myocardial infa rct ion , stroke and cardiovascular death . However , aspirin resistance may affect up to 45 % of the population . Little is known on the role of genetic factors that contribute to resistance or augmented response to aspirin in different human population s. METHODS In a large sample of nonsmoker , medication-free healthy volunteers from mainl and China ( n = 323 ; age : 22.1 + /- 2.0 years ) ( mean + /- st and ard deviation ) , we determined the frequency of polymorphisms in cyclooxygenase 1 ( COX1 ) ( A-842 G and C50 T ) , glycoprotein IIIa ( GPIIIa ) ( PLA1/A2 ) and purinergic receptor P2Y ( P2Y1 ) ( C893 T and A1622 G ) genes . These c and i date genes were chosen on the basis of their impact on platelet physiology and aspirin mode of action . A four panel P2Y1 genotype-stratified sample of healthy volunteers ( n = 24 in total ) , identified from the large study sample above , prospect ively received a 100 mg daily oral dose of aspirin for 7 days . We measured changes in platelet aggregation before and after aspirin treatment . As a comparison reference group , 6 out of 24 subjects in the prospect i ve aspirin trial had the P2Y1 CT893/AG1622 genotype that displays a low frequency ( < 7 % ) in the Chinese population . RESULTS COX1 A-842 G , C50 T and GPIIIa PLA1/A2 genetic polymorphisms were not observed in our sample from mainl and China . Allele frequencies of P2Y1 893 T and 1622 G were 3.5 and 30.6 % , respectively . The heterozygosity for the P2Y1 A1622 G polymorphism observed in the present study was different to Caucasians ; Chinese displayed a higher allele frequency for the 1622 G allele . After aspirin treatment , the net decrease in arachidonic acid-induced platelet aggregation was significantly larger in the P2Y1 CT893/AG1622 genotype panel ( 83.4 + /- 3.7 % , net reduction by aspirin expressed as percentage of baseline ) compared with CC893/GG1622 ( 68.2 + /- 13.5 % ) , CC893/AG1622 ( 68.9 + /- 9.6 % ) and CC893/AA1622 ( 65.1 + /- 9.1 % ) genotypic groups ( p = 0.012 , 0.025 and 0.004 , respectively ; statistical power = 77 % ) . There was no significant difference in antiplatelet effect of aspirin  among the CC893/GG1622 , CC893/AG1622 and CC893/AA1622 genotypes ( p > 0.05 ) . CONCLUSIONS The COX1 A-842 G , C50 T and GPIIIa PLA1/A2 polymorphisms are rare in Chinese . In contrast to previous studies in Caucasian population s , these c and i date functional polymorphisms are unlikely to be significant contributors to aspirin pharmacodynamics in Chinese persons . Importantly , the presence of the P2Y1 893CC genotype appears to confer an attenuated antiplatelet effect during aspirin treatment in healthy Chinese volunteers . These data collectively underscore the importance of population -to- population variability in clinical pharmacogenetics research and provide a basis for further long-term studies of aspirin response and P2Y1 genetic variation in patients with cardiovascular risk 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 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 BACKGROUND AND PURPOSE Antithrombotic therapy can prevent strokes and transient ischemic attacks ( TIAs ) in carefully selected patients who have chronic nonvalvular atrial fibrillation ( NVAF ) . Our objectives were 3-fold : to document the use of warfarin and aspirin therapy in Missouri Medicare beneficiaries with chronic NVAF ; to identify factors associated with warfarin and aspirin underuse ; and to determine the association between prescription of warfarin and aspirin at hospital discharge and adverse outcomes in this elderly , frail population . METHODS We linked chart review s from all Missouri hospitals to Medicare cl aims data from 1993 to 1996 . From chart review s , we documented Medicare beneficiaries ' demographic factors , comorbid conditions , and antithrombotic therapy prescribed at the time of hospital discharge . From Medicare cl aims , we determined the date of outcomes -death from any cause or hospitalization for an ischemic event ( a stroke , a TIA , or a myocardial infa rct ion ) . RESULTS Only 328 ( 55 % ) of the 597 Medicare beneficiaries were prescribed antithrombotic therapy at hospital discharge : 34 % received warfarin and 21 % received aspirin . Advanced age , female gender , and rural residency predicted underuse of antithrombotic therapy . After controlling for these factors , as well as stroke risk factors and contraindications to anticoagulation , the prescription of warfarin was associated with a 24 % relative risk reduction ( RRR ) in adverse outcomes ( P=0.003 ) . Prescription of aspirin was associated with a nonsignificant 5 % RRR in these events ( P=0.56 ) . CONCLUSIONS The underuse of antithrombotic therapy in Medicare beneficiaries who have NVAF is associated with measurable adverse outcomes . The benefit of warfarin therapy may extend to frail , elderly patients , a group that was excluded from r and omized controlled trials . The role of antiplatelet therapy in this population deserves further study because many of these patients have relative contraindications to warfarin OBJECTIVE To assess the prophylactic efficacy of aspirin and a high-dose antioxidant vitamin combination in patients with peripheral arterial disease ( PAD ) in terms of reduction of the risk of a first vascular event ( myocardial infa rct ion , stroke , vascular death ) and critical limb ischaemia . DESIGN R and omized , placebo-controlled , double-blind clinical trial with 2 x 2 factorial design . SETTING Thirty-seven European angiology/vascular medicine units . SUBJECTS A total of 366 out patients with stage I-II PAD documented by angiography or ultrasound , with ankle/brachial index < 0.85 or toe index < 0.6 ; 210 patients completed the follow-up . INTERVENTIONS Four treatment groups : ( i ) oral aspirin ( 100 mg daily ) , ( ii ) oral antioxidant vitamins ( 600 mg vitamin E , 250 mg vitamin C and 20 mg beta-carotene daily ) , ( iii ) both or ( iv ) neither , given for 2 years . MAIN OUTCOME MEASURE Major vascular events ( cardiovascular death , myocardial infa rct ion or stroke ) and critical leg ischaemia . RESULTS Seven of 185 patients allocated aspirin and 20 of 181 allocated placebo suffered a major vascular event ( risk reduction 64 % , P = 0.022 ) ; five and eight patients , respectively , suffered critical leg ischaemia ( total 12 vs. 28 , P = 0.014 ) . There was no evidence that antioxidant vitamins were beneficial ( 16/185 vs. 11/181 vascular events ) . Neither treatment was associated with any significant increase in adverse events . Inclusion of this trial in a meta- analysis of other r and omized trials of anti-platelet therapy in PAD makes the overall results highly significant ( P < 0.001 ) and suggests that low-dose aspirin reduces the incidence of vascular events by 26 % . CONCLUSIONS For the first time direct evidence shows that low-dose aspirin should routinely be considered for PAD patients , including those with concomitant type 2 diabetes BACKGROUND 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 Aspirin 's prevention of cardiovascular disease ( CVD ) events in individuals with type 2 diabetes mellitus is controversial . Eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) and aspirin all affect the cyclooxygenase enzyme . The relationship between plasma EPA and DHA and aspirin 's effects has not been determined . Thirty adults with type 2 diabetes mellitus ingested aspirin ( 81 mg/day ) for 7 days , then EPA+DHA ( 2.6g/day ) for 28 days , then both for another 7 days . Lysophosphatidic acid ( LPA ) species and more classic platelet function outcomes were determined . Plasma concentrations of total EPA+DHA were associated with 7-day aspirin reduction effects on these outcomes in a " V"-shaped manner for all 11 LPA species and ADP-induced platelet aggregation . This EPA+DHA concentration was quite consistent for each of the LPA species and ADP . These results support aspirin effects on lysolipid metabolism and platelet aggregation depending on plasma EPA+DHA concentrations in individuals with a disturbed lipid milieu Omega-3 fatty acids ( n-3 FA ) from oily fish are clinical ly useful for lowering triglycerides and reducing risk of heart attacks . Accordingly , patients at risk are often advised to take both aspirin and n-3 FA . However , both of these agents can increase bleeding times , and the extent to which the combination inhibits platelet function is unknown . The purpose of this pilot study was to determine the effects of a prescription omega-3 FA product ( P-OM3 ) and aspirin , alone and in combination , on platelet aggregation assessed by whole blood impedance aggregometry ( WBA ) . Ten healthy volunteers provided blood sample s on four separate occasions : Day 1 , baseline ; Day 2 , one day after taking aspirin ( 2 x 325 mg tablets ) ; Day 29 , after 28 days of P-OM3 ( 4 capsules/day ) ; and Day 30 , after one day of combined P-OM3 and aspirin . WBA was tested with two concentrations of collagen , with ADP and with a thrombin receptor activating peptide ( TRAP ) . Compared to baseline , aspirin alone inhibited aggregation only with low-dose collagen stimulation ; P-OM3 alone did not inhibit aggregation with any agonist ; and combined therapy inhibited aggregation with all agonists but TRAP . Significant interactions between interventions were not observed in response to any agonist . In conclusion , P-OM3 alone did not inhibit platelet aggregation , but did ( with two agonists ) when combined with aspirin . Since previous studies have not reported a clinical ly significant risk for bleeding in subjects on combined therapy , P-OM3 may safely enhance the anti-platelet effect of aspirin BACKGROUND In inhibiting platelet function , aspirin seems to reduce the risk of cerebrovascular accidents , death , and acute coronary events in patients with nonrheumatic atrial fibrillation .  Aspirin given on alternate days might have the advantage of not hindering prostacyclin synthesis . Thus a study was performed to evaluate whether aspirin used in this way might improve the results reported with daily treatment . METHODS To test this hypothesis 285 patients ( age range 40 to 82 years ) with primary atrial fibrillation were r and omly allocated in an open multicenter trial to 3 groups : ( 1 ) group A1 , treated with 125 mg aspirin daily ( n = 104 ) ; ( 2 ) group A2 , treated with 125 mg aspirin on alternate days ( n = 90 ) , ( 3 ) group C ( controls ) , who were not treated with anticoagulants or platelet inhibitors ( n = 91 ) . RESULTS Inclusion took place from January 1990 to July 1994 , and follow-up ended in May 1996 ( range 1 to 62 months ) . Sudden cardiac death in association with heart failure or angina was the most common final event : 4.8 % , 1.1 % , and 6.6 % in groups A1 , A2 , and C , respectively . Both cardiovascular mortality rate and the incidence of main events were reduced , in relative terms , by 80 % ( 1 . 1 % in group A2 vs 6.6 % in group C ) . The differences were smaller between group A1 and C but did not reach statistical significance . The reduction of main cardiovascular events between groups A1 and A2 was statistically significant ( 7.7 % vs 2.2 % = 5.5 % ; 95 % confidence limits 1 % , 11 % ; P < .05 ) . The difference did not reach statistical significance when other end points were analyzed . CONCLUSION In this trial low-dose aspirin given on alternate days seemed to be an efficient intervention in preventing major cardiovascular events . Regarding strokes , however , aspirin was less efficient . Mortality rate in the 3 groups as a whole was associated with heart failure and the development of ischemic heart disease Objective To determine the individual variability in the response to aspirin and /or clopidogrel and its impact on graft patency after off-pump coronary artery bypass grafting . Design A single-centre prospect i ve r and omised controlled study design ed according to the Consoli date d St and ards of Reporting Trials statement . R and omisation was obtained by a computer-generated algorithm . Setting University medical school in Italy . Patients 300 patients who underwent off-pump coronary artery bypass grafting were r and omised to receive aspirin ( n=150 ) or aspirin plus clopidogrel ( n=150 ) . Intervention Aspirin 100 mg or aspirin 100 mg plus clopidogrel 75 mg daily was initiated when postoperative chest tube drainage was ≤50 ml/h for 2 h and patients were followed up for 12 months . Main outcome measures Qualitative and quantitative assessment of platelet function , angiographic evaluation of coronary revascularisation by 64-slice CT and clinical outcome . Results In the aspirin group , 49 patients ( 32.6 % ) were aspirin resistant and , in the aspirin-clopidogrel group , 19 patients ( 12.6 % ) were aspirin and clopidogrel resistant . The platelet response to aspirin  was similar in all aspirin responders despite the study arm ( Aspirin Reaction Units 313.2±44.8 vs 323.6±53.6 ; p=0.07 ) . The platelet response to clopidogrel  was enhanced by aspirin in patients responsive to both aspirin and clopidogrel ( synergistic effect ) compared with responders to clopidogrel only ( P2Y12 Reaction Units 139.9±15.5 vs 179.4±18.5 ; p<0.001 ) . Combined therapy was associated with a reduced vein graft occlusion rate ( 7.4 % vs 13.1 % ; p=0.04 ) . Antiplatelet resistance was a predictor of graft occlusion ( RR 3.6 , 95 % CI 2.5 to 6.9 ; p<0.001 ) . Synergistic aspirin and clopidogrel activity was a strong predictor of vein graft patency ( RR 5.1 , 95 % CI 1.4 to 16.3 ; p<0.01 ) . Conclusions Combined clopidogrel and aspirin overcome single drug resistances , are safe for bleeding and improve venous graft patency Background Patients with chronic kidney disease ( CKD ) are at high risk for developing cardiovascular events . However , limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression . Study Design Prospect i ve , multicenter , open-label r and omized controlled trial . Setting and Participants One hundred eleven patients with estimated glomerular filtration rate ( eGFR ) 15–60 ml/min/1.73 m2 without previous cardiovascular events . InterventionAspirin treatment ( 100 mg/day ) ( n = 50 ) or usual therapy ( n = 61 ) . Mean follow-up time was 64.8 ± 16.4 months . Outcomes The primary endpoint was composed of cardiovascular death , acute coronary syndrome ( nonfatal MI , coronary revascularization , or unstable angina pectoris ) , cerebrovascular disease , heart failure , or nonfatal peripheral arterial disease . Secondary endpoints were fatal and nonfatal coronary events , renal events ( defined as doubling of serum creatinine , ≥ 50 % decrease in eGFR , or renal replacement therapy ) , and bleeding episodes . Results During follow-up , 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups , respectively . Aspirin did not significantly reduce primary composite endpoint ( HR , 0.396 ( 0.146–1.076 ) , p = 0.069 . Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group . Aspirin significantly reduced the risk of coronary events ( log-rank , 5.997 ; p = 0.014 ) . Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group . Aspirin treatment decreased renal disease progression in a model adjusted for age , baseline kidney function , and diabetes mellitus ( HR , 0.272 ; 95 % CI , 0.077–0.955 ; p = 0.043 ) but did not when adjusted for albuminuria . No differences were found in minor bleeding episodes between groups and no major bleeding was registered . Limitations Small sample size and open-label trial . Conclusions Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint ; however , there were reductions in secondary endpoints with fewer coronary events and renal outcomes . Clinical Trials.gov Identifier : NCT01709994 Inhibition of platelet thromboxane A(2 ) ( TXA(2 ) ) by aspirin is critical in patients with acute myocardial infa rct ion ( AMI ) , but some patients have persistent platelet TXA(2 ) production within 48 hours of the onset of AMI . Statins are known to reduce TXA(2 ) in aspirin-free patients with hypercholesterolemia . We hypothesized that treatment with aspirin plus atorvastatin could reduce persistent TXA(2 ) synthesis and aspirin resistance in patients with AMI . We evaluated  platelet function in 184 aspirin-treated patients within 48 hours of the onset of AMI . Patients were divided into group A  ( treated with aspirin alone , n = 139 ) and group B ( treated with aspirin plus atorvastatin  , n = 45 )  . We studied collagen-induced platelet TXA(2 ) synthesis , serotonin ( (14)C-5HT ) release and recruitment , and adenosine diphosphate- , arachidonic acid- , and collagen-induced platelet aggregation . Persistent TXA(2 ) synthesis was detected in 25 % and 9 % of groups A and B , respectively ( p = 0.03 ) . TXA(2 ) , arachidonic acid-aggregation , and collagen-induced responses were significantly reduced in patients receiving dual treatment compared to those receiving aspirin monotherapy . Atorvastatin did not modify platelet reactivity in patients with efficiently blocked TXA(2 ) synthesis . These results strongly suggest a direct effect of the statin on platelet eicosanoid synthesis . This was confirmed in vitro by incubating washed aspirin-free and aspirin ( 1 muM)-treated platelets from normal subjects with 1 to 20 microM atorvastatin . Atorvastatin in vitro significantly reduced platelet TXA(2 ) synthesis and collagen-induced aggregation . In conclusion , atorvastatin combined with aspirin early in the onset of the acute event significantly reduced persistent TXA(2 ) and TXA(2)-dependent aspirin resistance . This could contribute to the clinical benefit of atorvastatin in patients with AMI Background and Purpose — Aspirin is used commonly to prevent ischemic strokes and other vascular events . Although aspirin is considered safe and effective , it has limited efficacy with a relative risk reduction of 20 % to 25 % for ischemic stroke . We sought to determine if aspirin as currently used is having its desired antiplatelet effects . Methods — We ascertained patients with cerebrovascular disease who were taking only aspirin as an antiplatelet agent .  Platelet function was evaluated using a platelet function analyzer ( PFA-100 ) . PFA test results were correlated with aspirin dose , formulation , and basic demographic factors . Results — We ascertained 129 patients , of whom 32 % were taking an enteric-coated aspirin preparation and 32 % were taking low-dose ( ≤162 mg/d ) aspirin .  For the entire cohort , 37 % of patients had normal PFA-100 results , indicating normal platelet function . For the patients taking low-dose aspirin , 56 % had normal PFAs compared with 28 % of those taking ≥325 mg/d of aspirin , while 65 % of patients taking enteric-coated aspirin had normal PFAs compared with 25 % taking an uncoated preparation ( P < 0.01 for both comparisons ) . Similar results were obtained if PFA results were analyzed using mean closure times ( low-dose aspirin , 183 sec ; high-dose aspirin , 233 sec ; enteric-coated , 173 sec ; uncoated , 235 sec ; P < 0.01 for comparisons ) . Older patients and women were less likely to have a therapeutic response to aspirin , independent of aspirin dose or formulation . Conclusions — A significant proportion of  patients taking low-dose aspirin or enteric-coated aspirin  have normal platelet function as measured by the PFA-100 test . If these results correlate with clinical events , they have broad implication s in determining how aspirin is used and monitored Coronary artery bypass grafting is pivotal in the contemporary management of complex coronary artery disease . Interpatient variability to antiplatelet agents , however , harbors the potential to compromise the revascularization benefit by increasing the incidence of adverse events . This study was design ed to define the impact of dual antiplatelet therapy ( dAPT ) on clinical outcomes among aspirin-resistant patients who underwent coronary artery surgery .  We r and omly assigned 219 aspirin-resistant patients according to multiple electrode aggregometry to receive clopidogrel ( 75 mg ) plus aspirin ( 300 mg ) or aspirin-monotherapy ( 300 mg ) . The primary end point was a composite outcome of all-cause death , nonfatal myocardial infa rct ion , stroke , or cardiovascular hospitalization assessed at 6 months postoperatively . The primary end point occurred in 6 % of patients assigned to dAPT and 10 % of patients r and omized to aspirin-monotherapy ( relative risk 0.61 , 95 % confidence interval 0.25 to 1.51 , p = 0.33 ) . No significant treatment effect was noted in the occurrence of the safety end point . The total incidence of bleeding events was 25 % and 19 % in the dAPT and aspirin-monotherapy groups , respectively ( relative risk 1.34 , 95 % confidence interval 0.80 to 2.23 , p = 0.33 ) . In the subgroup analysis , dAPT led to lower rates of adverse events in patients with a body mass index > 30 kg/m(2 ) ( 0 % vs 18 % , p < 0.01 ) and those < 65 years ( 0 % vs 10 % , p = 0.02 ) . In conclusion , the addition of clopidogrel in patients found to be aspirin resistant after coronary artery bypass grafting did not reduce the incidence of adverse events , nor did it increase the number of recorded bleeding events . dAPT did , however , lower the incidence of the primary end point in obese patients and those < 65 years OBJECTIVES 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 Background — Thrombotic events still occur in  aspirin-treated patients with coronary artery disease . Methods and Results — To better underst and aspirin “ resistance , ” serum thromboxane B2 ( TXB2 ) and flow cytometric measures of arachidonic acid – induced platelet activation ( before and after the ex vivo addition of aspirin and indomethacin ) were analyzed in 700 consecutive aspirin-treated patients undergoing cardiac catheterization .  In 680 of 682 evaluable patients , serum TXB2 concentrations were reduced compared with nonaspirinated healthy donors . Twelve patients had serum TXB2 that was lower than nonaspirinated healthy donors but > 10 ng/mL. Arachidonic acid stimulated greater platelet activation in patients with high serum TXB2 ( > 10 ng/mL ) than in patients with low serum TXB2 . Addition of ex vivo aspirin  reduced arachidonic acid – induced platelet activation to similar levels regardless of serum TXB2 concentrations , which suggests that patients with high residual serum TXB2 concentrations were either noncompliant or underdosed with aspirin . Among the remaining 98 % of patients , ex vivo administration of either aspirin or indomethacin failed to prevent platelet activation across all degrees of arachidonic acid – induced platelet activation and aspirin doses . Although the patients were not r and omized with respect to clopidogrel treatment , multivariate analysis showed that arachidonic acid – induced platelet activation was less in patients receiving clopidogrel . Conclusions — There is a residual arachidonic acid – induced platelet activation  in aspirin-treated patients that ( 1 ) is caused by underdosing and /or noncompliance in only ≈2 % of patients and ( 2 ) in the remaining patients , occurs via a cyclooxygenase-1 and cyclooxygenase-2 independent pathway , in direct proportion to the degree of baseline platelet activation , and is mediated in part by adenosine diphosphate – induced platelet activation 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 Background : Aspirin-clopidogrel combination therapy inhibits platelet aggregation . The effect on platelet recruitment is unknown . Methods : Thirty chronic ischemic stroke patients taking aspirin alone followed by aspirin-clopidogrel combined therapy  had platelet reactivity tests performed over 3 months : ex vivo platelet aggregation , platelet recruitment and urinary 11-dehydro-thromboxane B2 (11-dhTxB2)excretion . Statistical analysis of variance compared platelet aggregation and recruitment between aspirin alone and aspirin-clopidogrel , and longitudinal regression analysis estimated platelet recruitment over time . Nonlinear mapping defined variable connections in each patient . Results : Statistically significant differences were found between aspirin alone and aspirin-clopidogrel for ( 1 ) adenosine-diphosphate- and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment and ( 2 ) increasing inhibition of platelet recruitment over time . Urinary 11-dhTxB2 excretion did not predict platelet aggregation response . Nonlinear mapping showed patient-unique variable interconnections . Conclusions : Platelet inhibition with aspirin-clopidogrel may increase over time , and future studies should focus on this finding in the context of vascular complications 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 Peripheral arterial disease ( PAD ) is associated with platelet hyperactivity . Aspirin and clopidogrel , two platelet inhibitors , act by different mechanisms . Aspirin inhibits thromboxane A2 synthesis and clopidogrel acts on the P2Y12 platelet ADP receptor . We evaluated the effect of clopidogrel ( 75 mg/day ) , aspirin ( 75 mg/day ) and then both drugs on several platelet function indices in patients with PAD ( n = 20 ) . There was a significant ( P = 0.0001 ) decrease in ADP-induced aggregation , after clopidogrel but not after taking aspirin . Clopidogrel plus aspirin significantly decreased spontaneous platelet aggregation ( SPA ) ( P = 0.01 to P = 0.002 ) but SPA was not significantly altered by either aspirin or clopidogrel monotherapy . Similarly , monotherapy did not inhibit serotonin (5HT)-induced aggregation but there was a significant inhibition ( P = 0.03 to P<0.02 ) after combination therapy . ADP ( 0.8 μM)-induced platelet shape change ( PSC ) was significantly inhibited by clopidogrel ( P = 0.004 ) or aspirin ( P = 0.01 ) . This was also true for 5HT-induced PSC  ( clopidogrel , P = 0.01 ; aspirin , P = 0.03 ) . Soluble P-selectin decreased significantly ( from 32 ± 24 to 25 ± 17 ng/ml , P = 0.04 ) with combination therapy . Plasma platelet-derived growth factor and intraplatelet 5HT levels were not altered by combination therapy . In PAD , clopidogrel is a more potent inhibitor of ADP-induced platelet activation than aspirin ; combination therapy is more effective than clopidogrel or aspirin monotherapy . These potentially clinical ly relevant findings should be evaluated in appropriately design ed trials 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 Aspirin is beneficial in the prevention and treatment of cardiovascular events , but patients who have events while taking aspirin  may have worse outcomes than those not on aspirin . We investigated the association between prior aspirin use and clinical outcomes in 9,461 patients with non-ST-elevation acute coronary syndromes enrolled in the Platelet IIb/IIIa in Unstable angina : Receptor Suppression Using Integrilin Therapy ( PURSUIT ) trial , before and after adjustment for baseline factors . We also examined whether eptifibatide has a differential treatment effect in prior aspirin users . Prior aspirin users were less likely to have an enrollment myocardial infa rct ion ( MI ) ( vs unstable angina ) ( 43.9 % vs 48.8 % , p = 0.001 ) but more likely to have death or MI at 30 days ( 16.1 % vs 13.0 % , p = 0.001 ) and at 6 months ( 19.9 % vs 15.9 % , p = 0.001 ) . After adjustment , prior aspirin users remained less likely to have an enrollment MI ( odds ratio 0.88 , 95 % confidence interval 0.79 to 0.97 ) and more likely to have death or MI at 30 days ( odds ratio 1.16 , 95 % confidence interval 1.00 to 1.33 ) but not at 6 months ( odds ratio 1.14 , 95 % confidence interval 0.98 to 1.33 ) . In a multivariable model , eptifibatide did not have a different treatment effect in prior aspirin users compared with nonusers ( p = 0.534 ) . Prior aspirin users had fewer enrollment MIs but worse long-term outcomes than nonusers . We found no evidence for a different treatment effect of eptifibatide in prior aspirin users OBJECTIVES Aspirin therapy is usually continued throughout the perioperative period to reduce the risk for thromboembolic stroke and myocardial infa rct ion after carotid endarterectomy ( CEA ) .  Aspirin irreversibly binds cyclooxygenase-1 , thereby reducing platelet aggregation for the lifetime of each platelet . However , recent research from this unit has shown that aggregation in response to arachidonic acid increases significantly , but transiently , during CEA , which suggests that the anti-platelet effect of aspirin is temporarily reversed . The purpose of the current study was to determine when this phenomenon occurs and to identify the possible mechanisms involved . METHODS Platelet aggregation was measured in platelet-rich plasma from 41 patients undergoing CEA who were stabilized with 150 mg of aspirin daily . Blood was taken at 8 time points : before anesthesia , after anesthesia , before heparinization , 3 minutes after heparinization , 3 minutes after shunt insertion , 10 minutes after flow restoration , 4 hours postoperatively , and 24 hours postoperatively . Platelet aggregation was also measured at similar times in a group of 18 patients undergoing peripheral angioplasty without general anesthesia .  RESULTS All patient platelets were effectively inhibited by aspirin at the start of the operation . There was a significant intraoperative increase in platelet response to arachidonic acid in both groups of patients , which occurred within 3 minutes of administration of unfractionated heparin . In the CEA group this result ed in a greater than 10-fold increase in mean aggregation , to 5 mmol/L of arachidonic acid ( 5 mmol/L ) , rising from 3.9 % + /- 2.2 % preoperatively to 45.1 % + /- 29.3 % after administration of heparin ( P < .0001 ) . This increased aggregation persisted into the early postoperative period , but by 24 hours post operation aggregation had returned to near preoperative values . Aggregation in response to other platelet agonists ( adenosine diphosphate , thrombin receptor agonist peptide ) showed only a small increase at the same time , which could be accounted for by a parallel increase in the level of spontaneous aggregation . CONCLUSION Administration of heparin significantly increases platelet aggregation in response to arachidonic acid , despite adequate inhibition by aspirin administered preoperatively . This apparent reversal in anti-platelet activity persisted into the immediate early postoperative period , and could explain why a small proportion of patients are at increased risk for acute cardiovascular events after major vascular surgery , despite aspirin therapy 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 : The antithrombotic , antiplatelet and endothelial activity of terutroban , a specific thromboxane prostagl and in receptor antagonist , was assessed in patients previously treated with aspirin for the prevention of ischemic stroke . Methods : This double-blind , parallel-group , 10-day study included 48 patients ( age = 70.5 ± 9.5 years ) with cerebral ischemic event and /or carotid stenosis in 4 groups :  terutroban 10 mg/day ( n = 13 ) , aspirin 300 mg/day ( n = 12 ) , terutroban 10 mg/day + aspirin 300 mg/day ( n = 11 ) or clopidogrel 75 mg/day + aspirin 300 mg/day ( n = 12 ) . The measurements included parameters from an ex vivo model of thrombosis , platelet aggregation in platelet-rich plasma and plasma biomarkers of endothelial/platelet activation . Results : Between days 0 and 10 , the mean cross-sectional surface of dense thrombus significantly decreased with terutroban ( 58 % , p = 0.001 ) , terutroban + aspirin ( 63 % , p = 0.005 ) and clopidogrel + aspirin ( 61 % , p < 0.05 ) . On day 10 , the value for terutroban was significantly lower than that for aspirin ( p < 0.01 ) and was comparable to the dual therapy terutroban + aspirin or clopidogrel + aspirin . Similar results were found for total thrombus surface and platelet adhesion . Platelet aggregation induced by the specific thromboxane prostagl and in receptor agonist U46619 was almost completely inhibited on day 10 in both terutroban groups but not in the others . As regards markers of endothelial/platelet activation or lesions , thrombomodulin significantly increased and plasma soluble P selectin significantly decreased by day 10 in both terutroban groups , whereas the von Willebr and factor did not change significantly . Terutroban was found to be safe and well tolerated . Conclusions : Terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to clopidogrel + aspirin ; it induces a significant in vivo reduction in endothelial/platelet activation The aim of this study was to assess whether triple antiplatelet therapy is superior to dual and mono therapy in attenuating platelet and leucocyte function .  Aspirin ( A ) , clopidogrel ( C ) , and dipyridamole ( D ) were administered singly and in various combinations ( A , C , D , AC , AD , CD , ACD ) , each for two weeks ( without washout ) to 11 healthy subjects and to 11 patients with previous ischaemic stroke in two r and omised multiway crossover trials . At the end of each two-week period platelet aggregation , platelet-leucocyte conjugate formation and leucocyte activation were measured ex vivo blinded to treatment . Platelets were stimulated with collagen ; additional measurements were made with adenosine diphosphate ( ADP ) , platelet activating factor ( PAF ) , adrenaline and the combination of , ADP , PAF and adrenaline . Results show that in the presence of collagen , ACD was superior to all antagonists or combinations , except AC , in reducing aggregation , platelet-leucocyte conjugate formation , and monocyte activation ( all p<0.05 ) . ACD was also more potent than other treatments , except AC , in inhibiting the aggregation and platelet-monocyte conjugate formation induced by the combination of ADP , PAF and adrenaline . The effects were similar in both volunteers and stroke patients .  No serious adverse events or major bleeding events occurred . Triple antiplatelet therapy did not appear to be more effective than combined aspirin and clopidogrel in moderating platelet and leucocyte function . Any additional clinical benefit provided by dipyridamole may be through other mechanisms of action Context In patients with unstable angina , combination therapy with clopidogrel plus aspirin has been shown to be more effective than aspirin alone in preventing myocardial infa rct ion , stroke , or cardiovascular death , but the cost-effectiveness of such therapy has yet to be determined . Contribution When the authors used a societal perspective and lifetime time horizon , combination therapy increased quality -adjusted life span at a cost that was within the traditionally accepted limits of cost-effectiveness . Caution s Data are not yet available to determine whether combination therapy for longer than 1 year remains cost-effective , due to the uncertainty of the relationship between long-term efficacy and risk for hemorrhage . The Editors The Clopidogrel  in Unstable Angina to Prevent Recurrent Events ( CURE ) trial demonstrated that clopidogrel plus aspirin was superior to aspirin alone in preventing the composite outcome of myocardial infa rct ion , stroke , or cardiovascular death in the year following an acute coronary syndrome or nonQ-wave myocardial infa rct ion ( 1 ) . Although combination therapy is recommended for such patients for at least 1 month , the optimal duration is less clear ( 2 ) . In addition , the cost of clopidogrel complicates the decision to combine it with aspirin . Adding clopidogrel to aspirin is financially unattractive if done in all patients with coronary disease ( 3 ) but may be cost-effective in high-risk patients , for whom clopidogrel offers more substantial absolute risk reduction . To assess the cost-effectiveness of clopidogrel plus aspirin relative to aspirin alone in high-risk patients with coronary artery disease and to explore the optimal duration of therapy , we constructed a decision analytic Markov model comparing these treatment strategies after an acute coronary syndrome as defined in CURE . Methods We performed a cost-effectiveness analysis using a Markov model ( 4 ) ( DATA 4.0 , TreeAge Software , Inc. , Williamstown , Massachusetts ) . We analyzed a reference case assuming a societal perspective ( 5 ) and a lifetime time horizon ( 6 ) . Our analysis was based on the CURE trial , a r and omized comparison of 3 to 12 months of therapy with clopidogrel plus aspirin or aspirin alone to prevent cardiovascular death , myocardial infa rct ion , or stroke in 12562 patients with an acute coronary syndrome ( 1 ) . We discounted costs and utilities at 3 % annually and determined lifetime costs , quality -adjusted life expectancy , and the incremental cost-effectiveness ratio . Sensitivity analyses included 1-way analyses on all data inputs ; probabilistic sensitivity analysis ; evaluation of varying duration of combination therapy , including potential loss of efficacy over time ; and consideration of population s with varying risk . Target Population The target population was analogous to that of the CURE trial ( 1 ) : patients with an acute coronary syndrome characterized by electrocardiographic changes or elevated serum cardiac markers in association with chest pain . Patients who had prolonged ST-segment elevation , who had undergone revascularization in the previous 3 months , who were at risk for severe bleeding or heart failure , or who had been treated with oral anticoagulants or glycoprotein IIb/IIIa inhibitors in the preceding 3 days were excluded . On the basis of the average age of CURE patients , we considered a 64-year-old as our base case and explored other ages in sensitivity analysis . We compared treatment costs and clinical outcomes for 2 types of antiplatelet therapy : 1 ) aspirin alone , 325 mg/d , and 2 ) clopidogrel , 75 mg/d , plus aspirin , 325 mg/d , for 1 year , followed by aspirin monotherapy . Model Structure In our model , we included vascular events : myocardial infa rct ion , stroke , vascular death and revascularization , intracerebral and gastrointestinal hemorrhagic events , and clopidogrel-associated thrombotic thrombocytopenic purpura . We included age-related mortality , correcting for events explicitly included in the model . We did not directly include procedures or outcomes , such as congestive heart failure , that CURE did not specifically address ( 1 ) . We indirectly accounted for the cost of such events by using age-adjusted annual health care costs ( 7 ) . This assumes equal probability of such events in each arm of the analysis . We allowed for multiple events , including multiple events of a particular type , within a given monthly cycle . We created Markov states for conditions that changed quality of life , annual cost , or probability of future events . For events with temporary decrements in quality of life , we assessed a utility toll proportional to the duration of hospitalization required ( 8) . We also modeled each combination of 2 events . When more than 2 events occurred , we used the Markov state that combined the 2 events with the lowest utility ( Figure 1 ) . Figure 1 . Schematic representation of the decision model . Model Inputs Probabilities We derived probabilities for vascular and hemorrhagic events over the first year of our analysis from the CURE trial ( 1 ) . Rates of cardiovascular outcomes were highest in the month immediately following the acute coronary syndrome ( 1 ) . To account for temporal variation in risk , we calculated probabilities for the first month separately from those for subsequent months . Beyond the time frame of the CURE trial , we empirically calculated declining probability functions for myocardial infa rct ion , cardiovascular death , and revascularization on the basis of proportional decline in risk over time in survivors of nonQ-wave myocardial infa rct ion ( 9 ) . We assumed that all bleeding events , other than intracerebral hemorrhage , were gastrointestinal . Because intracerebral hemorrhage was equally likely for the 2 treatment strategies ( 1 ) , all of the excess bleeding in the clopidogrel plus aspirin arm was attributed to gastrointestinal causes . The rate of thrombotic thrombocytopenic purpura associated with clopidogrel was derived from an observational study ( 10 , 11 ) . We represented uncertainty in event rates through distributions based on the number of events that occurred and the number of patient-years at risk . We obtained age-specific mortality from life tables ( 12 ) and corrected for death rates of events explicitly included in our model ( Table ) . Table . Model Inputs Efficacy of Combination Therapy Despite the variation in risk , the relative efficacy of clopidogrel plus aspirin did not vary between the first and subsequent months ( 1 ) . In modeling beyond the time frame of the CURE trial , we assumed in our base case that efficacy remained constant , on the basis of data for clopidogrel monotherapy ( 13 ) . We explored waning efficacy over time in sensitivity analysis . We used 3 variables to describe loss of efficacy , duration of constant efficacy ( 1 year to lifetime ) , duration of efficacy deterioration ( 1 to 10 years ) , and the extent of efficacy decline relative to  aspirin monotherapy ( none to complete loss ) . Costs We derived costs for each event and for chronic care of disabled patients from the literature . For medications , we used the average wholesale price in the United States as our base value ( 35 ) and considered prices negotiated by a large-volume purchaser in constructing the price range . Acute care costs for clinical events represent the direct costs of all medical care incurred during hospitalization . Chronic care costs represent direct expenditures for medications , procedures , and nursing care specific to the condition in question and were assessed for each month in the Markov state . For Markov states representing survival after either severe stroke or intracerebral hemorrhage and another event , we assumed 20 % of the long-term cost of the additional condition to account for overlapping therapy . We accounted for other health care costs by using age-adjusted annual health expenditures ( 7 ) . We up date d costs to 2002 U.S. dollars with a gross domestic product deflator ( 44 ) and generated log-normal distributions for each estimate for use in sensitivity analyses ( Table ) . Utilities We used published population -based utilities , representing either time-tradeoff or st and ard-gamble techniques . For Markov states representing 2 events , we combined utilities with multiplication ( 8) . For events and procedures that did not result in durable changes in the health state of the individual , we used disutility tolls based on the average duration of hospitalization ( 8) . We modeled uncertainty in utility estimates by calculating distributions based on the range of utility estimates in the literature ( Table ) . Sensitivity Analyses To assess the degree to which variation in any variable altered our results , we performed 1-way sensitivity analyses for each model input by analyzing the results at both extremes of its 95 % CI . In evaluating patients of different ages , we adjusted both age-related mortality and estimates of annual health care cost accordingly . To better underst and the distribution of the cost-effectiveness ratio for clopidogrel plus aspirin and the potential value of further research , we performed probabilistic sensitivity analysis using Monte Carlo simulation ( 45 , 46 ) . In each of 1000 simulations , the value for each model input was r and omly selected from its distribution . We constructed a cost-effectiveness acceptability curve by calculating the average net monetary benefit for each strategy in each simulation over cost-effectiveness thresholds ranging from no additional expenditure for the least expensive therapy to $ 100000 for each quality -adjusted life-year ( QALY ) gained . We then determined the proportion of simulations for which clopidogrel plus aspirin result ed in the greater net monetary benefit at each cost-effectiveness threshold . We also assessed varying the duration of  clopidogrel therapy from 1 month to 1 year in monthly increments . We considered prolonged therapy , up to patient lifetime , in yearly increments , simultaneously assessing potential decline in the efficacy of clopidogrel . To better PURPOSE The efficacy and safety of new antiplatelet therapies , as well as antiplatelet therapies in development , are review ed . SUMMARY Variability in the response to treatment with aspirin has been recognized for more than 40 years . Thienopyridine antiplatelet agents are now a st and ard pharmacologic component in the management of patients undergoing percutaneous coronary intervention ( PCI ) and stent placement . However , investigators have recently described wide inter-individual variability in the level of platelet inhibition following treatment with the thienopyridine clopidogrel , with a small number of patients classified as " non-responders " or " resistant . " Such variability in response is likely to have important clinical implication s , because antiplatelet therapy plays a key role in the prevention and treatment of cardiovascular disease , For example , recent studies have demonstrated that diminished response to clopidogrel may be associated with increased cardiac events after PCI . Even with larger-than-approved loading doses , clopidogrel requires several hours to reach a steady-state effect , and therapy must be discontinued for several days prior to surgery in order to avoid major bleeding events . Clinical trials of prasugrel , a new oral thienopyridine with a more rapid onset of platelet inhibition , have demonstrated significant reductions in adverse cardiovascular outcomes and stent thrombosis ; however , there is an increased risk for major bleeding events with prasugrel in some subgroups of the study population s. These limitations have led to development of agents that may potentially overcome such clinical challenges . AZD6140 , a novel , potent oral P2Y12 antagonist , demonstrated more effective platelet inhibition versus clopidogrel in a large r and omized trial of patients with acute coronary syndrome . However , patients taking AZD6140  reported dyspnea significantly more frequently than those taking clopidogrel . Cangrelor , a novel intravenous P2Y(12 ) receptor antagonist with a rapid onset of action and complete reversibility of platelet inhibition within 20 - 50 minutes of administration , may offer advantages over currently approved antiplatelet therapies . A new oral antiplatelet thrombin-receptor antagonist , TRA-SCH 530348 , is in early clinical trials . Unlike currently available drugs , TRA-SCH 530348 effectively prevents thrombin-induced activation of platelets . CONCLUSION Each new class of antiplatelet therapies has the potential for specific benefits and adverse effects in clinical use OBJECTIVE We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes . RESEARCH DESIGN AND METHODS The Primary Prevention Project ( PPP ) is a r and omized , open trial with a two-by-two factorial design aim ed to investigate low-dose aspirin ( 100 mg/day ) and vitamin E ( 300 mg/day ) in the prevention of cardiovascular events in patients with one or more cardiovascular risk factors . The primary end point was a composite end point of cardiovascular death , stroke , or myocardial infa rct ion . A total of 1,031 people with diabetes in the PPP , aged > /=50 years , without a previous cardiovascular event were enrolled by 316 general practitioners and 14 diabetes outpatient clinics . RESULTS The PPP trial was prematurely stopped ( after a median of 3.7 years ) by the independent data safety and monitoring board because of a consistent benefit of aspirin compared with the control group in a population of 4,495 patients with one or more major cardiovascular risk factors . In diabetic patients , aspirin treatment was associated with a nonsignificant reduction in the main end point ( relative risk [ RR ] = 0.90 , 95 % CI 0.50 - 1.62 ) and in total cardiovascular events ( 0.89 , 0.62 - 1.26 ) and with a nonsignificant increase in cardiovascular deaths ( 1.23 , 0.69 - 2.19 ) . In nondiabetic subjects , RRs for the main end point , total cardiovascular events , and cardiovascular deaths were 0.59 ( 0.37 - 0.94 ) , 0.69 ( 0.53 - 0.90 ) , and 0.32 ( 0.14 - 0.72 ) , respectively . No significant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects . CONCLUSIONS Our data suggest a lower effect of primary prevention of cardiovascular disease ( CVD ) with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors . If confirmed , these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation , thus making the balance between benefits and harms of aspirin treatment unfavorable . Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed 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 BACKGROUND Antiplatelet drugs are recommended for patients with acute noncardioembolic stroke . However , few r and omized clinical trials have investigated the safety and efficacy of dual antiplatelet therapy for these patients . The aim of this study was to evaluate the effects of treatment with clopidogrel and aspirin ( combination therapy ) and aspirin alone ( monotherapy ) on neurologic deterioration , platelet activation , and other short-term outcomes in patients with acute large-artery atherosclerosis stroke . MATERIAL S AND METHODS Altogether 574 patients with acute ( ≤2 days ) large-artery atherosclerosis stroke were r and omly assigned to receive either combined clopidogrel and aspirin or aspirin alone . Platelet aggregation and platelet-leukocyte aggregation studies were performed at days 1 and 30 . Primary outcomes including recurrent ischemic stroke , neurologic deterioration , periphery vascular events , and myocardial infa rct ion were monitored . Safety endpoints were hemorrhagic episodes and death . RESULTS The prevalence of neurologic deterioration and recurrent ischemic stroke were lower in patients in the combination therapy group than in those of the monotherapy group ( 3.52 % versus 9.78 % and 1.76 % versus 6.29 % , respectively ) . At day 30 of treatment , the platelet aggregations and platelet-leukocyte aggregates were lower in patients who were treated with clopidogrel and aspirin than in patients given aspirin alone ( P < .001 ) . CONCLUSIONS For patients with acute large-artery atherosclerosis stroke , treatment with clopidogrel and aspirin for 1 month provided significantly greater inhibition of platelet activity  than aspirin alone . Thus , dual therapy can be safer and more effective in reducing ischemic stroke recurrence and neurologic deterioration BACKGROUND The mechanisms for the variability in antiplatelet effects of aspirin are unclear . Immature ( reticulated ) platelets may modulate the antiplatelet effects of aspirin through uninhibited cyclooxygenase (COX)-1 and COX-2 . OBJECTIVES To evaluate the role of reticulated platelets in the antiplatelet effects of aspirin . METHODS Sixty healthy volunteers had platelet studies performed before and 24 h after a single 325-mg dose of aspirin . Platelet studies included light transmission aggregometry ; P-selectin and integrin alpha(IIb)beta(3 ) expression , and serum thromboxane B(2 ) ( TxB(2 ) ) levels . Reticulated platelets and platelet COX-2 expression were measured using flow cytometry . RESULTS Subjects were divided into tertiles based on the percentage of reticulated platelets in whole blood . Baseline platelet aggregation to 1 microg mL(-1 ) collagen , and postaspirin aggregations to 5 microm and 20 microm ADP and collagen , were greater in the upper than in the lower tertile of reticulated platelets . Stimulated P-selectin and integrin alpha(IIb)beta(3 ) expression were also higher in the upper tertile both before and after aspirin . Platelet COX-2 expression was detected in 12 + /- 7 % ( n = 10 ) of platelets in the upper tertile , and in 7 + /- 3 % ( n = 12 ) of platelets in the lower two tertiles ( P = 0.03 ) . Postaspirin serum TxB(2 ) levels were higher in the upper ( 5.5 + /- 4 ng mL(-1 ) ) than in the lower tertile ( 3.2 + /- 2.5 ng mL(-1 ) , P = 0.03 ) , and decreased even further with ex vivo additional COX-1 and COX-2 inhibition . The incidence of aspirin resistance ( > or= 70 % platelet aggregation to 5 microm ADP ) was significantly higher in the upper tertile ( 45 % ) than in the lower tertile ( 5 % , P < 0.0001 ) . CONCLUSIONS Reticulated platelets are associated with diminished antiplatelet effects of aspirin and increased aspirin resistance , possibly because of increased reactivity , and uninhibited COX-1 and COX-2 activity OBJECTIVES The objectives of this double-blind , placebo-controlled , r and omized dose-ranging study were 1 ) to examine the safety and tolerability of tirofiban ( MK-383 ) , a new nonpeptide platelet IIb/IIIa receptor antagonist , on a background of intravenous heparin and aspirin therapy ; 2 ) to study the pharmacodynamics and pharmacokinetics of tirofiban ; and 3 ) to evaluate the incidence of adverse cardiac outcomes ( urgent repeat revascularization , myocardial infa rct ion and death ) with tirofiban versus placebo in a high risk subset of patients undergoing coronary angioplasty . BACKGROUND Abrupt vessel closure complicates 4 % to 8 % of angioplasty procedures . Recent data have suggested that agents that antagonize the platelet glycoprotein IIb/IIIa receptor may reduce the incidence of adverse ischemic outcomes after coronary angioplasty . METHODS Seventy-three patients received tirofiban in three sequential dose panels and 20 patients received placebo . Patients within each panel were r and omized to receive either tirofiban or placebo in a 3:1 r and omization design . Bolus doses of 5 , 10 and 10 microg/kg and continuous infusion ( 16 to 24 h ) doses of 0.05 , 0.10 and 0.15 microg/kg per min were administered in panels I , II and III , respectively . Patients received concomitant heparin and aspirin for the angioplasty procedure . Data on patients receiving placebo ( heparin and aspirin only ) were pooled across panels for comparisons . The pharmacodynamic effect of tirofiban on ex vivo platelet aggregation to 5 micromol/liter adenosine diphosphate ( ADP ) and bleeding times were measured . Clinical outcomes were assessed in all patients , but the power to detect clinical ly meaningful differences ( a one-third reduction in clinical events ) between groups was limited ( 5 % ) . RESULTS Tirofiban was associated with a dose-dependent inhibition of ex vivo ADP-mediated platelet aggregation that was sustained during intravenous infusion and resolved rapidly after drug cessation . Adverse bleeding events , largely related to vascular access site hemorrhage , were slightly increased at the highest dose . Adverse clinical outcomes were infrequent in all patients and were not different among the small number of patients within each group . CONCLUSIONS This study establishes a rational and generally well tolerated dosing regimen for administration of tirofiban as adjunctive therapy in high risk angioplasty patients . The impact of tirofiban on adverse clinical outcomes after angioplasty awaits definition by a larger clinical trial Aspirin has an established benefit in reducing the incidence of coronary events and vein graft occlusion . We have now assessed the risk of pre-operative aspirin in a prospect i ve , r and omised , double-blind clinical trial in 100 patients scheduled for elective coronary artery surgery . Any prescribed aspirin and non-steroidal anti-inflammatory drugs were discontinued 2 weeks pre-operatively and these were replaced by a r and omly assigned tablet of either aspirin 300 mg daily or placebo taken until the day of surgery . Patient compliance was confirmed by serum and urinary salicylate analysis . The two groups were similar in demographic characteristics , bypass time , number of grafts placed and number of internal mammary arteries used . All patients  survived to be discharged home ( see Table ) . Aspirin decreases platelet aggregation to arachidonic acid and to collagen both pre- and post-operatively . The benefit of pre-operative aspirin has to be balanced against the risk of increasing post-operative blood loss , re-exploration for excessive bleeding and transfusion requirements Background The naturally-occurring omega (ω)-3 polyunsaturated fatty acid ( PUFA ) eicosapentaenoic acid ( EPA ) reduces colorectal adenoma ( polyp ) number and size in patients with familial adenomatous polyposis . The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong c and i date for colorectal cancer ( CRC ) chemoprevention , alone or in combination with aspirin , which itself has recognized anti-CRC activity . Colorectal adenoma number and size are recognized as biomarkers of future CRC risk and are established as surrogate end-points in CRC chemoprevention trials . Design The seAFOod Polyp Prevention Trial is a r and omized , double-blind , placebo-controlled , 2 × 2 factorial ‘ efficacy ’ study , which will determine whether EPA prevents colorectal adenomas , either alone or in combination with aspirin .  Participants are 55–73 year-old patients , who have been identified as ‘ high risk ’ ( detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter ) at screening colonoscopy in the English Bowel Cancer Screening Programme ( BCSP ) . Exclusion criteria include the need for more than one repeat endoscopy within the three-month BCSP screening period , malignant change in an adenoma , regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs , regular use of fish oil supplements and concomitant warfarin or anti-platelet agent therapy . Patients are r and omized to either EPA-free fatty acid 1 g twice daily or identical placebo AND aspirin 300 mg once daily or identical placebo , for approximately 12 months . The primary end-point is the number of participants with one or more adenomas detected at routine one-year BCSP surveillance colonoscopy . Secondary end-points include the number of adenomas ( total and ‘ advanced ’ ) per patient , the location ( left versus right colon ) of colorectal adenomas and the number of participants re-classified as ‘ intermediate risk ’ for future surveillance . Exploratory end-points include levels of bioactive lipid mediators such as ω-3 PUFAs , resolvin E1 and PGE-M in plasma , urine , erythrocytes and rectal mucosa in order to gain insights into the mechanism(s ) of action of EPA and aspirin , alone and in combination , as well as to discover predictive biomarkers of chemopreventive efficacy . The recruitment target is 904 patients .Trial Registration Current Controlled Trials IS RCT OBJECTIVES We sought to compare the inhibitory effects of the combination of two doses of aspirin plus clopidogrel with either drug alone on platelet aggregation and activation . BACKGROUND Enhanced platelet inhibitory effects of clopidogrel by aspirin on platelet aggregation and activation are suggested by experimental studies but have not been shown in humans . METHODS The effects of clopidogrel 75 mg or aspirin 100 ( 300 ) mg on platelet aggregation and activation by flow cytometry after stimulation with various agonists were determined in 30 patients with a past history of myocardial infa rct ion . RESULTS Clopidogrel alone or in combination with aspirin markedly inhibited adenosine diphosphate (ADP)-mediated platelet aggregation compared with monotherapy with aspirin ( 24.6 + /- 3.3 % or 26.6 + /- 2.7 % vs. 44.7 + /- 2.9 % ; p < 0.001 ) . Combined treatment significantly inhibited collagen-induced aggregation compared with aspirin and clopidogrel ( 16.4 + /- 2.4 % , 36.5 + /- 4.2 % and 59.3 + /- 5.1 % , respectively ; , p < 0.001 ) and result ed in considerable inhibition of aggregation induced by thrombin receptor agonist peptide ( TRAP , p < 0.03 ) . Clopidogrel with or without aspirin significantly suppressed expression of platelet activation markers CD 62p , CD 63 and PAC-1 after stimulation with ADP or thrombin ( p < 0.001 ) . In addition , the combined treatment was more effective than either agent alone after activation with low dose thrombin ( p < 0.05 ) . Both doses of aspirin equally potentiated the platelet inhibitory effects of clopidogrel . CONCLUSIONS In this prospect i ve clinical ex vivo platelet study , clopidogrel was more effective than aspirin in inhibiting ADP-mediated platelet aggregation and activation .  Clopidogrel in combination with aspirin showed synergistic inhibitory effects after stimulation with collagen and thrombin compared with monotherapies . Thus , this dual antiplatelet treatment strategy deserves further evaluation in clinical trials for secondary prevention of acute myocardial infa rct ion or unstable angina OBJECTIVE To determine the incremental cost-effectiveness of clopidogrel plus aspirin ( C + A ) compared with aspirin ( A ) alone during the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ( CHARISMA ) trial from a US payer perspective . BACKGROUND Although the CHARISMA trial did not find a benefit of adding clopidogrel to aspirin in its overall study cohort , a benefit was suggested in a prespecified subgroup of patients with established cardiovascular ( CV ) disease . The cost-effectiveness of dual antiplatelet therapy in this population is unknown . METHODS Medical re source utilization was assessed prospect ively , and costs for hospitalizations , physician services , outpatient care , and medications were assigned using 2007 US dollars . Life expectancy was estimated contingent on fatal and nonfatal CV events using statistical models of long-term survival from the Saskatchewan Health data base . RESULTS C + A was associated with a 12.5 % relative reduction in CV death , myocardial infa rct ion , or stroke compared with A alone ( 6.9 % vs. 7.9 % , P = 0.048 ) over a median 28 months of follow-up . Severe or moderate bleeding events were higher in patients receiving C + A versus A alone ( 3.6 % vs. 2.5 % , P < 0.001 ) . Mean cost/patient was $ 2607 higher for C + A , while projected life expectancy increased by an average of 0.072 years due to fewer in-trial events . The result ing incremental cost-effectiveness ratio ( ICER ) for C + A was $ 36,343/year of life gained . Findings were insensitive to discount rate , life expectancy projections , post-event costs , and indirect costs from lost productivity ; the ICER was most sensitive to the cost of clopidogrel . Bootstrap analysis demonstrated that the ICER for C + A remained < $ 50,000/life-year gained in 70.6 % of bootstrap replicates and < $ 100,000/life-year gained in 87.4 % . CONCLUSIONS Among patients with established CV disease , adding clopidogrel to aspirin appears to increase life expectancy modestly at a cost generally considered acceptable within the US health-care system 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 – 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 AIMS Although full platelet inhibition with aspirin and thienopyridines before coronary stenting has significantly reduced the risk of acute stent thrombosis , peri-procedural myonecrosis still occurs frequently and is associated with increased death rate . Whether further inhibition of platelet aggregation by a glycoprotein IIb/IIIa antagonist may provide an additional cardioprotection is unknown . METHODS AND RESULTS A total of 200 patients pre-treated with aspirin and a loading dose of clopidogrel ( 450 mg ) were r and omized just before coronary intervention ( percutaneous coronary intervention , PCI ) to treatment with  or without abciximab .  Platelet aggregation was assessed in sample s collected during the procedure and the degree of platelet aggregation inhibition was correlated with cardiac enzyme release post-PCI . Abciximab treatment achieved a more complete inhibition of aggregation than dual oral antiplatelet therapy alone ( median value of 1 vs. 50 % , normal 100 % ) . Any pathological increase in creatinine kinase-MB ( CK-MB ) post-PCI was present in 21 % of the abciximab group and in 22 % of the no-abciximab group ( P = 0.9 ) . Also the occurrence of clinical ly relevant myonecrosis [ myocardial infa rct ion ( MI ) = CK-MB > 3x upper limit of normal ] was not significantly influenced by treatment assignment : 9 vs. 10 % ( P = 0.9 ) . In a multiple logistic regression model including clinical , angiographic , and procedural characteristics , post-PCI myonecrosis was not correlated with the degree of platelet aggregation inhibition but with procedural features ( such as long inflation time ) and with the presence of multi-vessel disease . There were no cases of acute or subacute stent thrombosis . At 6 months , major adverse cardiac events , including cardiac death , non-fatal MI , or target lesion revascularization occurred in 13 % of abciximab patients and in 16 % of the control patients ( P = 0.6 ) . CONCLUSIONS In the studied patients scheduled for elective coronary stenting and pre-treated with aspirin and a loading dose of clopidogrel , further inhibition of platelet aggregation by abciximab does not afford additional cardioprotection . Our data suggest that distal athero-embolization rather than thrombo-embolization is involved in the phenomenon of myonecrosis post-elective stenting 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 OBJECTIVES We sought to examine the effects of escalating doses of omega-3 polyunsaturated fatty acid ( PUFA ) supplements on platelet function using light transmission aggregometry ( LTA ) and electrophoretic quasi-elastic light scattering technology ( EQELS ) . BACKGROUND PUFA may inhibit platelet function through fatty acid substitution in the platelet membrane by changing the surface charge density and causing decreased production of thromboxane A2 . EQELS can measure platelet surface charge density and determine whether the platelet is in resting or activated state . METHODS A total of 30 volunteers were divided in 3 groups of 10 as follows : Group A , no antiplatelet agent ; Group B , daily aspirin only , and Group C , daily aspirin and clopidogrel . All patients received escalating doses of omega-3PUFA from 1 to 8 g daily over 24 weeks . Platelet function was measured by template bleeding time , LTA , and EQELS at baseline and at 6 , 12 , 18 and 24 weeks . RESULTS Mean bleeding time increased in a dose-dependent manner with escalating omega-3 PUFA doses . LTA confirmed expected antiplatelet effects of aspirin and clopidogrel , but did not detect any additional antiplatelet effects of omega-3 PUFA . EQELS showed a significant increase in the negative resting platelet charge compared to baseline and an attenuated response to arachidonic acid mediated platelet activation . No bleeding events were observed . CONCLUSIONS In this pilot study we were able to successfully measure platelet surface charge variation as a measure of omega-3 PUFA effect on platelets . Our results suggest that omega-3 PUFA increase the total platelet surface charge and , therefore , attenuate platelet activation , even among patients taking aspirin or aspirin plus clopidogrel . Further studies are needed to determine the clinical significance of these measured effects and EQELS results Background and Purpose — Clopidogrel is widely used in patients after recent ischemic stroke ; however , its ability to yield additional antiplatelet protection on top of aspirin has never been explored in a controlled study . To determine whether clopidogrel with aspirin ( C+ASA ) will produce more potent platelet inhibition than aspirin alone ( ASA ) in patients after ischemic stroke , we conducted the Plavix Use for Treatment of Stroke trial . Methods — Seventy patients after ischemic stroke were r and omly assigned to C+ASA or ASA groups . Platelet studies included aggregometry ; cartridge-based analyzers ; expression of PECAM-1 , P-selectin , GP IIb/IIIa ( antigen and activity ) , vitronectin receptor , and formation of platelet-leukocyte microparticles by flow cytometry . Platelet tests were performed at baseline and after 30 days after r and omization . Results — There were no deaths , hospitalizations , or serious adverse events . There were no differences in the baseline platelet characteristics between C+ASA and ASA groups , or significant changes in platelet parameters in the ASA group , except diminished collagen-induced aggregation ( P=0.001 ) . In contrast , therapy with C+ASA result ed in a significant inhibition of platelet activity assessed by ADP- ( P=0.00001 ) and collagen-induced ( P=0.02 ) aggregation ; closure time prolongation ( P=0.03 ) , and reduction of platelet activation units with Ultegra ( P=0.00001 ) ; expression of PECAM-1 ( P=0.01 ) , and GP IIb/IIIa activity with PAC-1 ( P=0.02 ) when compared with ASA group . Therapy with C+ASA also result ed in the reduced formation of platelet – leukocyte microparticles ( P=0.02 ) . Conclusion — Treatment with C+ASA for 1 month provides significantly greater inhibition of platelet activity than ASA alone in patients after recent ischemic stroke in the frame of the small r and omized trial PURPOSE We sought to investigate the association of aspirin dose and aspirin resistance in stable coronary artery disease patients measured by a point-of-care assay . METHODS We studied 468 consecutive stable coronary artery disease patients in a referral cardiac center who were taking aspirin 80 to 325 mg daily for > or = 4 weeks .  The VerifyNow Aspirin ( Ultegra RPFA-ASA , Accumetrics Inc , San Diego , Calif ) was used to determine aspirin responsiveness . An aspirin reaction unit ( ARU ) > or = 550 indicates the absence of aspirin-induced platelet dysfunction , based on correlation with epinephrine-induced light transmission aggregometry . Demographic and clinical data were collected to analyze the predictors of aspirin resistance . RESULTS  Aspirin resistance was noted in 128 ( 27.4 % ) patients . Univariate predictors of aspirin resistance include elderly ( P = 0.002 ) , women ( P < 0.001 ) , anemia ( P < 0.001 ) , renal insufficiency ( P = 0.009 ) and aspirin dose < or = 100 mg ( P = 0.004 ) . Multivariate analysis revealed hemoglobin ( odds ratio [ OR ] 0.6 ; 95 % confidence interval [ CI ] 0.51 to 0.69 ; P < 0.001 ) and aspirin dose < or = 100 mg ( OR 2.23 ; 95 % CI 1.12 to 4.44 ; P = 0.022 ) to be independent predictors of aspirin resistance . Daily aspirin dose < or = 100 mg was associated with increased prevalence of aspirin resistance compared with 150 mg and 300 mg daily ( 30.2 % vs 16.7 % vs 0 % , P = 0.0062 ) . CONCLUSION A 100 mg or less daily dose of aspirin , which may have lower side effects , is associated with a higher incidence of aspirin resistance in patients with coronary artery disease . Prospect i ve r and omized studies are warranted to eluci date the optimal aspirin dosage for preventing ischemic complications of atherothrombotic disease
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 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 .