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
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
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 .