title: Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Incidence of aspirin nonresponsiveness using the Ultegra Rapid Platelet Function Assay-ASA. Antiplatelet Effect of Aspirin in Patients With Cerebrovascular Disease Low-dose aspirin increases aspirin resistance in patients with coronary artery disease. Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Screening for Aspirin Responsiveness After Transient Ischemic Attack and Stroke: Comparison of 2 Point-of-Care Platelet Function Tests With Optical Aggregometry Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. In vitro aspirin resistance detected by PFA‐100TM closure time: pivotal role of plasma von Willebrand factor Relation of aspirin resistance to coronary flow reserve in patients undergoing elective percutaneous coronary intervention. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
abstract: 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 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 We report the incidence of  aspirin  nonresponsiveness  in a prospect i ve , multicenter registry ( n=422 patients ) to be 23 % using the Ultegra Rapid Platelet Function Assay-ASA , and determined a history of coronary artery disease to be associated with twice the odds of being an  aspirin nonresponder ( odds ratio 2.01 , 95 % confidence interval 1.189 to 3.411 , p=0.009 ) . Further prospect i ve studies are needed to correlate  aspirin nonresponsiveness to adverse clinical events Background and Purpose — Aspirin is used commonly to prevent ischemic strokes and other vascular events . Although aspirin is considered safe and effective , it has limited efficacy with a relative risk reduction of 20 % to 25 % for ischemic stroke . We sought to determine if aspirin as currently used is having its desired antiplatelet effects . Methods — We ascertained patients with cerebrovascular disease who were taking only aspirin as an antiplatelet agent .  Platelet function was evaluated using a platelet function analyzer ( PFA-100 ) . PFA test results were correlated with aspirin dose , formulation , and basic demographic factors . Results — We ascertained 129 patients , of whom 32 % were taking an enteric-coated aspirin preparation and 32 % were taking low-dose ( ≤162 mg/d ) aspirin .  For the entire cohort , 37 % of patients had normal PFA-100 results , indicating normal platelet function . For the patients taking low-dose aspirin , 56 % had normal PFAs compared with 28 % of those taking ≥325 mg/d of aspirin , while 65 % of patients taking enteric-coated aspirin had normal PFAs compared with 25 % taking an uncoated preparation ( P < 0.01 for both comparisons ) . Similar results were obtained if PFA results were analyzed using mean closure times ( low-dose aspirin , 183 sec ; high-dose aspirin , 233 sec ; enteric-coated , 173 sec ; uncoated , 235 sec ; P < 0.01 for comparisons ) . Older patients and women were less likely to have a therapeutic response to aspirin , independent of aspirin dose or formulation . Conclusions — A significant proportion of  patients taking low-dose aspirin or enteric-coated aspirin  have normal platelet function as measured by the PFA-100 test . If these results correlate with clinical events , they have broad implication s in determining how aspirin is used and monitored PURPOSE We sought to investigate the association of aspirin dose and aspirin resistance in stable coronary artery disease patients measured by a point-of-care assay . METHODS We studied 468 consecutive stable coronary artery disease patients in a referral cardiac center who were taking aspirin 80 to 325 mg daily for > or = 4 weeks .  The VerifyNow Aspirin ( Ultegra RPFA-ASA , Accumetrics Inc , San Diego , Calif ) was used to determine aspirin responsiveness . An aspirin reaction unit ( ARU ) > or = 550 indicates the absence of aspirin-induced platelet dysfunction , based on correlation with epinephrine-induced light transmission aggregometry . Demographic and clinical data were collected to analyze the predictors of aspirin resistance . RESULTS  Aspirin resistance was noted in 128 ( 27.4 % ) patients . Univariate predictors of aspirin resistance include elderly ( P = 0.002 ) , women ( P < 0.001 ) , anemia ( P < 0.001 ) , renal insufficiency ( P = 0.009 ) and aspirin dose < or = 100 mg ( P = 0.004 ) . Multivariate analysis revealed hemoglobin ( odds ratio [ OR ] 0.6 ; 95 % confidence interval [ CI ] 0.51 to 0.69 ; P < 0.001 ) and aspirin dose < or = 100 mg ( OR 2.23 ; 95 % CI 1.12 to 4.44 ; P = 0.022 ) to be independent predictors of aspirin resistance . Daily aspirin dose < or = 100 mg was associated with increased prevalence of aspirin resistance compared with 150 mg and 300 mg daily ( 30.2 % vs 16.7 % vs 0 % , P = 0.0062 ) . CONCLUSION A 100 mg or less daily dose of aspirin , which may have lower side effects , is associated with a higher incidence of aspirin resistance in patients with coronary artery disease . Prospect i ve r and omized studies are warranted to eluci date the optimal aspirin dosage for preventing ischemic complications of atherothrombotic disease 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 Background and Purpose — Recent studies suggest that patients who do not respond to aspirin ( ASA ) therapy may be at increased risk of ischemic vascular events . The availability of simple to use point-of-care ( POC ) platelet function tests now potentially allows aspirin nonresponsiveness to be identified in routine clinical practice . However , there are very few data on whether the different tests produce consistent results . We therefore compared 2 POC tests ( PFA-100 device and the Ultegra-RPFA [ RPFA ] ) with conventional light transmission aggregometry ( LTA ) . Methods — Platelet function was assessed by all 3 tests in 100 patients receiving low-dose ASA therapy after transient ischemic attack ( TIA ) or ischemic stroke . Results — The incidence of ASA nonresponsiveness was 17 % by the RPFA and 22 % by the PFA-100 , compared with only 5 % by LTA ( ie , as defined with both arachidonic acid and ADP ) . Agreement between the RPFA and the PFA-100 and arachidonic acid induced LTA was poor ( & kgr;=0.16 , 95 % CI , −0.08 to 0.39 , P=0.11 ; and & kgr;=0.09 −0.12 to 0.30 , P=0.32 , respectively ) . Agreement between the 2 POC tests was also poor ( & kgr;=0.14 , −0.08 to 0.36 , P=0.15 ) . Only 2 % of patients were aspirin nonresponders by all 3 tests . Conclusions — The prevalence of apparent ASA nonresponsiveness was higher with both the POC tests than with LTA . However , agreement between the tests was poor and very few patients were ASA nonresponsive by all 3 tests . Aspirin nonresponsiveness is therefore highly test-specific and large prospect i ve studies will be required to determine the prognostic value of each of the separate tests 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 INTRODUCTION The purpose of the present study was to study the concept of aspirin resistance or non-responsiveness by investigating the response to long-term aspirin therapy in patients with a former acute myocardial infa rct ion ( AMI ) . MATERIAL S AND METHODS Patients with an AMI ( n=202 ) r and omly assigned to aspirin 160 mg/day ( n=71 ) , aspirin 75 mg/day and warfarin ( INR 2.0 - 2.5 ) ( n=58 ) or warfarin ( INR 2.8  - 4.2 ) ( n=73 ) were evaluated by the PFA-100(R ) , biochemical variables and clinical events after a mean treatment period of 4 years . RESULTS The limit for being an aspirin non-responder was defined as the 95th percentile value in the warfarin alone group ( 196 s ) with the epinephrine cartridge . In patients on aspirin alone 25/71 ( 35 % ) were non-responders and on the combination 23/58 ( 40 % ) . With the adenosine diphosphate ( ADP ) cartridge only minor differences were found . The levels of thromboxane B(2 ) in both aspirin groups , in responders as well as in non-responders , were extremely low compared to the warfarin alone group . Evaluating both aspirin groups together ( n=129 ) , the levels of soluble P-selectin were significantly higher in non-responders as compared to responders ( p=0.012 ) . During the observation period of 4 years with limited number of events , there was a tendency for higher event rates in non-responders as compared to responders ( 36 % vs. 24 % , p=0.28 ) . CONCLUSIONS In our evaluation of the PFA-100(R ) a considerable number of post-AMI patients seemed to be non-responders to long-term aspirin therapy in doses of 75 and 160 mg/day . Circulating levels of P-selectin were higher in the non-responders . A tendency to higher incidence of clinical events among non-responders was observed 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 The in vitro closure time ( CT ) , determined by the Platelet Function Analyzer ( PFA‐100TM ) , is used to monitor patients treated with aspirin . A relatively high percentage of in vitro aspirin resistance was reported despite an adequate inhibition of platelet response to arachidonic acid and we investigated whether high plasma levels of von Willebr and factor ristocetin cofactor activity ( vWF : RCo ) may contribute to this profile . Platelet aggregation test , CT [ collagen adrenaline ( CEPI‐CT ) and collagen adenosine 5′‐diphosphate ( ADP ) ( CADP‐CT ) ] , and vWF : RCo levels were evaluated in 55 consecutive patients receiving aspirin ( 75–250 mg/d ) versus 32 untreated control subjects . All the aspirin‐treated patients showed platelet aggregation responses that reflected the aspirin intake . However , CT data analysis enabled aspirin good‐responder ( GR ) and aspirin bad‐responder ( BR ) patients to be identified . All GR group subjects ( n = 27 ) , had a CEPI‐CT and a CADP‐CT longer than 300 s and 96 s respectively . The BR group ( n = 28 ) had CEPI‐CT values below 200 s and all CADP‐CT were in the normal range ( 77 ± 19 s ) . Interestingly , the BR plasma vWF : RCo levels were significantly higher ( 159 ± 43 % ) than those of the GR group ( 121 ± 34 % ) ( P < 0·01 ) , which were similar to control values ( 114 ± 31 % ) . A negative correlation between vWF : RCo and CT values was established . We demonstrate that in vitro  aspirin‐resistance , revealed by PFA‐100TM CT prolongation failure , is correlated to increased plasmatic vWF : RCo levels , reinforcing its particular importance in PFA‐100TM cartridges performance Previous studies have shown that more complete platelet inhibition improves the coronary flow reserve ( CFR ) , a measure of microvascular integrity , in patients undergoing percutaneous coronary intervention ( PCI ) . We hypothesized that patients with aspirin resistance would have impaired CFR after elective PCI . We used VerifyNow Aspirin to determine the response to aspirin in 117 consecutive patients who underwent elective single-lesion PCI . The assay results are expressed quantitatively in Aspirin Reaction Units based on the degree of platelet aggregation . All patients received a 300-mg loading dose of clopidogrel > 12 hours before and a 75-mg maintenance dose the morning of PCI . CFR was estimated using the Thrombolysis In Myocardial Infa rct ion frame count method . Of the 117 patients , 22 ( 18.8 % ) were aspirin resistant . The clinical , angiographic , and procedural characteristics of the aspirin-sensitive and -resistant patients were balanced . All patients underwent successful PCI with < 50 % residual diameter stenosis and Thrombolysis In Myocardial Infa rct ion grade 3 flow after PCI . Aspirin-resistant patients had a lower CFR than the aspirin-sensitive patients ( 1.42 + /- 0.35 vs 1.80 + /- 0.64 , p = 0.018 ) . Univariate correlates of CFR included the Aspirin Reaction Unit ( r = -0.227 , p = 0.014 ) and post-PCI creatine kinase-MB elevation ( p = 0.048 ) . Multivariate linear regression analysis revealed the Aspirin Reaction Unit to be the only independent determinant of CFR after PCI ( r2 = 0.051 , p = 0.014 ) . Thus , aspirin resistance was associated with impaired CFR in patients who underwent elective PCI , implicating insufficient aspirin-induced platelet inhibition as a cause of microvascular dysfunction by distal atherothrombotic embolization and /or spasm The hypothesis that aspirin resistance is often due to noncompliance was investigated . One hundred ninety patients with a history of myocardial infa rct ion were evaluated using arachidonic acid-stimulated light aggregometry at 3 different time points : while receiving their usual daily aspirin , after not receiving aspirin for 7 days , and 2 hours after the observed ingestion of aspirin 325 mg . At the first time point , 17 patients ( 9 % ) failed to show  aspirin inhibition of platelet aggregation , but 2 hours after observed aspirin ingestion ,  aspirin inhibition was observed in all but 1 patient
target: Prevalences widely differ between studies reporting on aspirin resistance .
background: 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 .