Protocol for a systematic review of the diagnostic and prognostic utility of tests currently available for the detection of aspirin resistance in patients with established cardiovascular or cerebrovascular disease Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. Aspirin resistance and diabetes mellitus A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Association of Cyclooxygenase-1–Dependent and –Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization Risk stratification after coronary artery bypass surgery by a point-of-care test of platelet function. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. 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. Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR) Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Aspirin, Statins, or Both Drugs for the Primary Prevention of Coronary Heart Disease Events in Men: A CostUtility Analysis Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer Abnormal PFA-100 closure time is associated with increased platelet aggregation in patients presenting with chest pain Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin "resistance". Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial. Profile and prevalence of aspirin resistance in patients with cardiovascular disease.
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
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 .