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 Aspirin resistance and diabetes mellitus Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR) The Effect of Aspirin Dosing on Platelet Function in Diabetic and Nondiabetic Patients Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Prevalence of platelet nonresponsiveness to aspirin in patients treated for secondary stroke prophylaxis and in patients with recurrent ischemic events. 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 Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in Stent Thrombosis (CREST) registry Risk stratification after coronary artery bypass surgery by a point-of-care test of platelet function. Aspirin resistance measured by cationic propyl gallate platelet aggregometry and recurrent cardiovascular events during 4 years of follow-up. Unstable angina, stroke, myocardial infarction and death in aspirin non‐responders. A prospective, randomized trial. The ASCET (ASpirin non‐responsiveness and Clopidogrel Endpoint Trial) design Earlier application of loading doses of aspirin and clopidogrel decreases rate of recurrent cardiovascular ischemic events for patients undergoing percutaneous coronary intervention. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. Aspirin resistance in Indian patients with coronary artery disease and cardiovascular events. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. The effects of aspirin and clopidogrel response on myonecrosis after percutaneous coronary intervention: a BRIEF-PCI (Brief Infusion of Intravenous Eptifibatide Following Successful Percutaneous Coronary Intervention) trial substudy. 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 Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance. Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer 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 
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 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 - 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 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 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 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 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 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 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 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 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 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 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 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 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 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 BACKGROUND Aspirin resistance is a major problem and its incidence and clinical significance in Indian patients with documented coronary artery disease are not known . AIM We sought to study the incidence of aspirin resistance and its clinical significance in a cohort of Indian patients with coronary heart disease on therapy with aspirin  using urinary 11-Dehydrothromboxane B2 levels as a surrogate marker for antiplatelet efficacy . SETTING AND DESIGN Non r and omized single center prospect i ve study in cohort of patients with stable cardiovascular disease on chronic aspirin therapy attending the cardiology outpatient clinic of a tertiary care hospital . MATERIAL S AND METHODS Urinary dehydrothromboxane levels were analyzed in a cohort of 63 patients with stable documented coronary artery disease and in 21 healthy volunteers . The cases were followed up prospect ively for a median period of 36 ( 1 - 53 ) months . The clinical endpoint was a composite of acute coronary syndrome , stroke , revascularization and death . STATISTICAL ANALYSIS Comparison of urinary dehydrothromboxane concentration values between various risk factors was done using Mann Whitney U test , a non parametric alternative of independent t test . All statistical analyses were done using SPSS 11.0 ( Chicago , USA ) software . RESULTS The median ( range ) absolute values of urinary11- dehydrothromboxane B2 levels for the healthy volunteers and cases were 440 ( 286 - 2050 ) pg/ml and 320 ( 72 - 2600 ) pg/ml ( P=0.007 ) . The corresponding normalized values were 87.3 ( 43 - 143 ) and 60.8 ( 16.7 - 943 ) ng/mmol of creatinine ( P=0.131 ) . Among the various vascular risk factors , patients who were overweight had higher absolute levels of 11- urinary dehydrothomboxane B2 levels ( P=0.016 ) . There were significantly more clinical events in patients with absolute urinary 11-dehydrothromboxane B2 levels in the upper two quartiles compared to the lower two quartiles ( P=0.04 ) . CONCLUSION The incidence of aspirin resistance in the cohort of patients with documented heart disease was 38.1 % . Patients with elevated absolute urinary dehydrothomboxane levels ( > 320 pg/ml ) on chronic aspirin therapy constitute a high risk subset for recurrent vascular events BACKGROUND 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 OBJECTIVES The purpose of this study was to evaluate the effects of aspirin and clopidogrel response on  myonecrosis after percutaneous coronary intervention ( PCI ) with glycoprotein ( GP ) IIb/IIIa blockade . BACKGROUND Aspirin and clopidogrel resistance is increasingly recognized , but its effects on PCI outcomes with GP IIb/IIIa blockade are unknown . METHODS This was a prospect i ve , pre-specified sub study of the BRIEF-PCI ( Brief Infusion of Intravenous Eptifibatide Following Successful Percutaneous Coronary Intervention ) trial , which r and omized 624 patients to 18-h or < 2-h eptifibatide infusion after uncomplicated PCI . To be eligible , patients must have been pre-treated with aspirin ( > or=5 days ) and clopidogrel ( 75 mg/day > or=5 days , 300 mg loading > or=6 h , or 600 mg loading > or=2 h ) and must not have received GP IIb/IIIa inhibitors within 48 h. Verify-Now Aspirin and Clopidogrel ( P2Y(12 ) ) assays were performed at baseline before PCI . Patients with aspirin reaction unit ( ARU ) > or=550 were labeled as aspirin resistant . Clopidogrel low-responders were defined as those in the lowest quartile of platelet inhibition . The primary end point was the prevalence of myonecrosis within 24 h after PCI . RESULTS We enrolled 209 patients into our sub study , of which 185 had aspirin response assessed , 198 had clopidogrel response assessed , and 174 had both assessed . There were 4.9 % who were aspirin resistant . Clopidogrel low-responders were defined as those in the lowest quartile with platelet inhibition < 19 % . Only 1.1 % had both aspirin resistance and low clopidogrel response . There was no difference in myonecrosis prevalence among aspirin-resistant compared with aspirin-sensitive patients ( 11.1 % vs. 27.8 % , p = 0.259 ) or among clopidogrel low-responders compared with clopidogrel responders ( 23.5 % vs. 29.3 % , p = 0.433 ) . CONCLUSIONS Aspirin and clopidogrel response did not affect myonecrosis prevalence amongst patients who received eptifibatide for PCI Background — 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 BACKGROUND Late venous graft thrombosis , leading to recurrent ischemia , is frequently encountered in old , degenerated vein grafts with advanced atherosclerotic plaque formation . Aspirin has been indicated to maintain venous graft patency in the post-operative period . However , there is considerable evidence that aspirin resistance is of concern in patients with venous grafts . MATERIAL AND METHOD Prospect ively enrolled 14 patients ( 11 male , 3 female , Group 1 ) , who were shown to have at least one occluded saphenous vein graft on their late control coronary angiogram after bypass operation , were compared for the presence of aspirin resistance by PFA-100 with age- and sex-matched 14 patients ( 10 male , 4 female , Group 2 ) , who were found patent and well-functioning vein grafts without wall irregularities on late post-operative coronary angiograms ( mean 6.5+/-2.5 years ) , enrolled as a control group . RESULTS Mean CT of collagen/epinephrine cartridge in Group 1 was 197+/-85 s and significantly less than in Group 2 ( 279+/-44 s ; p=0.011 ) . It was found that 50 % of patients in Group 1 were so-called aspirin resistant , whereas in Group 2 , this ratio was 7.1 % ( p=0.033 ) . BMI ( p=0.038 , Beta=-0.322 ) , uric acid level ( p=0.023 , Beta=-0.355 ) , and CT by collagen/epinephrine cartridge ( p=0.008 , Beta=0.431 ) were independently predicting late occlusion of saphenous vein graft . CONCLUSION Aspirin resistance is highly prevalent in patients with occluded venous grafts at a relatively late period 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 — 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
Prevalences widely differ between studies reporting on aspirin resistance .
BACKGROUND The absolute risk of recurrences among patients using aspirin for prevention of cardiovascular events remains high .
Persistent platelet reactivity despite aspirin therapy might explain this in part .
Reported prevalences of this so-called aspirin resistance vary widely , between 0 % and 57 % .
OBJECTIVES The aim of the study was to systematic ally review all available evidence on prevalence of aspirin resistance and to study determinants of reported prevalence .