Alternate-day dosing of aspirin in atrial fibrillation. LASAF Pilot Study Group. Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding Aspirin therapy: optimized platelet inhibition with different loading and maintenance doses. Anti-Platelet Effects of 100 mg Alternate Day Oral Aspirin: A Randomized, Double-Blind, Placebo-Controlled Trial of Regular and Enteric Coated Formulations in Men and Women Prevention of thrombosis in patients on hemodialysis by low-dose aspirin. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Antiplatelet Effect of Aspirin in Patients With Cerebrovascular Disease Low-dose aspirin increases aspirin resistance in patients with coronary artery disease. Effects of low-dose aspirin on in vitro platelet aggregation in the early minutes after ingestion in normal subjects. Low-Molecular-Weight Heparin or Dual Antiplatelet Therapy Is More Effective Than Aspirin Alone in Preventing Early Neurological Deterioration and Improving the 6-Month Outcome in Ischemic Stroke Patients Discharge aspirin dose and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel: an analysis from the TRITON-TIMI 38 study (trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Serial Urinary 11-Dehydrothromboxane B2, Aspirin Dose, and Vascular Events in Blacks After Recent Cerebral Infarction The Physician's Health Study. A neurologist's concern. Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease
BACKGROUND In inhibiting platelet function , aspirin seems to reduce the risk of cerebrovascular accidents , death , and acute coronary events in patients with nonrheumatic atrial fibrillation .  Aspirin given on alternate days might have the advantage of not hindering prostacyclin synthesis . Thus a study was performed to evaluate whether aspirin used in this way might improve the results reported with daily treatment . METHODS To test this hypothesis 285 patients ( age range 40 to 82 years ) with primary atrial fibrillation were r and omly allocated in an open multicenter trial to 3 groups : ( 1 ) group A1 , treated with 125 mg aspirin daily ( n = 104 ) ; ( 2 ) group A2 , treated with 125 mg aspirin on alternate days ( n = 90 ) , ( 3 ) group C ( controls ) , who were not treated with anticoagulants or platelet inhibitors ( n = 91 ) . RESULTS Inclusion took place from January 1990 to July 1994 , and follow-up ended in May 1996 ( range 1 to 62 months ) . Sudden cardiac death in association with heart failure or angina was the most common final event : 4.8 % , 1.1 % , and 6.6 % in groups A1 , A2 , and C , respectively . Both cardiovascular mortality rate and the incidence of main events were reduced , in relative terms , by 80 % ( 1 . 1 % in group A2 vs 6.6 % in group C ) . The differences were smaller between group A1 and C but did not reach statistical significance . The reduction of main cardiovascular events between groups A1 and A2 was statistically significant ( 7.7 % vs 2.2 % = 5.5 % ; 95 % confidence limits 1 % , 11 % ; P < .05 ) . The difference did not reach statistical significance when other end points were analyzed . CONCLUSION In this trial low-dose aspirin given on alternate days seemed to be an efficient intervention in preventing major cardiovascular events . Regarding strokes , however , aspirin was less efficient . Mortality rate in the 3 groups as a whole was associated with heart failure and the development of ischemic heart disease Context The optimal aspirin dose for prevention of cardiovascular events is unknown . Contribution This post hoc analysis of CHARISMA trial data suggests no overall differences in efficacy or safety by aspirin dose . However , in the subgroup of patients r and omly assigned to clopidogrel , there was a hint of reduced efficacy and increased harm with higher doses . Caution Patients were not r and omly assigned to aspirin dose . Implication Lower aspirin doses ( 75 to 81 mg/d ) may optimize efficacy and safety for patients requiring aspirin for long-term prevention , especially those taking clopidogrel .  The Editors Aspirin is the most widely used drug worldwide for the prevention of thrombotic cardiovascular events . Of note , the doses of aspirin used most often clinical ly or recommended in guidelines are based not on the results of trials design ed to identify the most efficacious or safest dose , but on a combination of historical precedents and trials in which specific doses of aspirin were m and ated by protocol . This practice has led to a wide range in aspirin doses ( 75 to 325 mg/d ) recommended by the U.S. Food and Drug Administration ( 1 ) for the management of cardiovascular disease in various population s. Although as little as 30 mg of aspirin daily is needed to fully inhibit platelet thromboxane production ( 2 ) , doses more than 10 times higher than this are routinely used in long-term prevention of cardiovascular disease . Because aspirin has been used clinical ly for more than a century and is a mainstay of therapy for patients who have or are at risk for atherosclerotic disease and other common ailments , its risks are often underappreciated . However , given that more than one third of U.S. adults are estimated to take aspirin daily for cardiovascular disease ( 3 ) , even a very small incidence of hemorrhagic complications places a large number of people at risk . Consistent with this is a recent analysis of hospitalizations for adverse drug effects that found aspirin to be one of the most common causal agents ( 4 ) . The gastrointestinal tract is the leading source of bleeding events in  aspirin-treated  patients because of inhibition of gastroprotective prostacyclins , with an excess risk for upper gastrointestinal complications of 5 cases per 1000 aspirin users per year ( 5 ) . Prospect i ve evaluation of  aspirin-treated patients with coronary artery disease identified an incidence of upper gastrointestinal bleeding of 1.5 % per year , with substantial associated morbidity ( 6 ) . Because inhibition of gastric prostacyclin is dose-dependent and not maximal until a daily dose of about 1300 mg is reached ( 4 ) , minimizing the dose of aspirin to that needed to fully inhibit platelet thromboxane production would probably offer the greatest potential benefit with the lowest possible risk . In several observational studies of large prospect i ve trials , lower doses of aspirin ( < 162 mg/d ) have been associated with the lowest incidence of thrombotic events ( 7 , 8) and a trend toward fewer bleeding events ( 8) . These favorable trends in efficacy and safety were confirmed in the CURE ( Clopidogrel in Unstable angina to prevent Recurrent Events ) trial ( 9 ) of dual antiplatelet therapy with clopidogrel plus aspirin versus placebo plus aspirin . On the basis of these results , the design of the CHARISMA ( Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ) trial ( 10 ) , which r and omly assigned 15603 patients at high risk for atherothrombotic events to clopidogrel or placebo in conjunction with aspirin , m and ated a daily aspirin dose of 75 to 162 mg . We performed a post hoc analysis of associations between investigator-determined daily aspirin dose and thrombotic and hemorrhagic outcomes in the prospect i ve CHARISMA trial . Methods The design , methods , and primary results of the CHARISMA study are reported elsewhere ( 10 ) . In brief , CHARISMA was a multicenter , double-blind , r and omized , placebo-controlled trial of long-term clopidogrel ( 75 mg/d ) treatment versus placebo in patients 45 years or older who had established atherosclerotic disease or were asymptomatic but at high risk because of a combination of risk factors . All patients also received low-dose aspirin therapy , which was limited by protocol to between 75 and 162 mg/d . Patients were excluded if they had an established indication for clopidogrel therapy , such as a recent acute coronary syndrome or stent implantation . Clinical follow-up was done at 1 , 3 , and 6 months and every 6 months thereafter until the end of the trial . The actual dose of aspirin being taken was confirmed at each evaluation . The ethics committee at each of the 768 participating hospitals worldwide , as well as the appropriate national ethics committee for each of the 32 participating countries , review ed and approved the study protocol . All patients provided written informed consent before enrollment . The primary efficacy end point was the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . The primary safety end point was severe or life-threatening bleeding according to the GUSTO-I ( Global Utilization of Streptokinase and TPA for Occluded coronary arteries ) criteria ( 11 ) : intracerebral bleeding or bleeding result ing in substantial hemodynamic compromise requiring treatment . A secondary safety end point was the combined incidence of severe or life-threatening bleeding or moderate bleeding by the GUSTO-I criteria , with moderate defined as bleeding requiring transfusion but not result ing in hemodynamic compromise ( 11 ) . Of note , patients believed to be at high risk for bleeding were excluded from enrollment .  Aspirin dose was not r and omized ; rather , it was selected at the discretion of the treating physician . We prospect ively divided patients into 3 major groups according to clear demarcations in aspirin dose at baseline : less than 100 mg/d , represented almost entirely by doses of either 75 or 81 mg/d ; 100 mg/d ; and greater than 100 mg/d , represented by either 150 or 162 mg/d . We evaluated the relative efficacy and safety of the different doses of aspirin among all patients , and we evaluated the efficacy and safety end points between the treatment ( clopidogrel ) versus placebo groups by aspirin dose category . Statistical Analysis We performed all data analyses on the intention-to-treat population . We performed hypothesis tests by using 2-sided tests at the 5 % significance level . Baseline characteristics were compared by using chi-square tests for discrete variables and t tests for continuous variables . We calculated cumulative KaplanMeier estimates of the event rates and assessed differences in the unadjusted rates of primary efficacy and safety end points across the aspirin groups by using a 2-sided log-rank test . We used log-rank weights to compute a test for trend across aspirin dose categories . We estimated the treatment effect , measured by the hazard ratio and its 95 % CI , by using the Cox proportional hazards model . Multivariable modeling was performed to determine whether aspirin dose was independently associated with the primary efficacy and safety outcomes after controlling for potentially confounding factors . Because patients could have had more than 1 efficacy or safety event , we defined the time to the primary efficacy end point as the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . We defined the time to the primary safety end point as the first occurrence of severe or life-threatening bleeding according to the GUSTO-I criteria ( 11 ) . We selected variables for inclusion in the models on the basis of differences in baseline characteristics among patients in the 3 aspirin dose categories or their clinical relevance to the outcomes . Covariates included in the multivariable model for the primary efficacy end point were the continuous variables of age , weight , and systolic blood pressure and the categorical variables of sex ; race or ethnicity ( white or Hispanic vs. other ) ; hypertension ; hypercholesterolemia ; history of congestive heart failure ; previous myocardial infa rct ion ; previous stroke ; previous transient ischemic attack ; diabetes mellitus ; atrial fibrillation ; peripheral arterial disease ; diabetic nephropathy ; current smoking ; primary ( vs. secondary ) prevention and past use of statins , nitrates , and antiplatelet agents other than aspirin . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by aspirin dose category . Adjustment variables in the multivariable model for the primary safety end point ( GUSTO-I severe or life-threatening bleeding ) included age and weight as continuous variables and the categorical variables of stable angina with multivessel disease , sex , race or ethnicity ( white or Hispanic vs. other ) , history of congestive heart failure , previous myocardial infa rct ion , previous stroke , previous transient ischemic attack , diabetes mellitus , atrial fibrillation , peripheral arterial disease , diabetic nephropathy , hypertension , hypercholesterolemia , primary prevention ( vs. secondary ) , and current smoking . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by daily aspirin dose category . To adjust for geographical region without estimating its effect , we used region ( categorized as United States , Canada , Western Europe , Eastern Europe , Latin America , Asia and Australia , or Africa ) as a stratification variable in models for both end points . We assessed the interaction of  aspirin dose and r and omized treatment in both models . We calculated and tested the difference between the maximum likelihood ratios with and without 2 interaction terms ( r and omized treatment assignment by daily aspirin dose of 100 mg and greater than 100 mg ) . We assessed proportional hazards by multiplying each covariate by the log of the time to the event . A Wald test was performed to test the linear hypotheses of the regression coefficients . The proportional Inhibition of cyclooxygenase by aspirin has been shown to be beneficial in clinical situations such as acute myocardial infa rct ion or unstable angina . The precise effect of various doses of aspirin on acute and long-term inhibition of platelet aggregation and thromboxane synthesis remains unclear . In this study we evaluated the effect of oral aspirin ( 0 , 40 , 100 , 300 , or 500 mg ) as the initial loading dose in combination with different maintenance doses of aspirin ( 0 , 40 , or 100 mg/day ) for 14 days on platelet function in healthy men .  Bleeding time 2 or 24 hours after the first aspirin administration was significantly increased for 300 and 500 mg aspirin ( p < 0.01 ) . Two hours after the first administration of 100 , 300 , and 500 mg aspirin , a significant inhibition of collagen-induced platelet aggregation ( ED50 collagen : from 3 + /- 1 to 17 + /- 2 , 24 + /- 3 , 22 + /- 3 micrograms/ml , respectively ) was seen . At the same time serum thromboxane B2 synthesis was inhibited by more than 99 % with 300 and 500 mg aspirin . At the end of the 14-day observation period , bleeding time was significantly prolonged for the different combinations of aspirin doses compared with initial values ( p < 0.01 ) . Collagen-induced platelet aggregation and serum thromboxane B2 synthesis were significantly inhibited for all aspirin combinations tested at 14 days ( p < 0.05 ) . The 40/40 mg aspirin combination was less effective , because it reached its maximal effect very late at day 7 of the observation period compared with the other combinations . ( ABSTRACT TRUNCATED AT 250 WORDS Aim While regular use of low-dose aspirin has been recommended for several groups of patients at risk of vascular occlusion , the optimal dose of aspirin to produce a cardiovascular benefit whilst minimizing side effects is uncertain . Further , while enteric coated preparations may reduce gastrointestinal symptoms , the antiplatelet effects of these formulations have not been completely tested . In addition , exceptionally few data relating to these issues have been available in women . Methods To determine whether a 100 mg alternate day dose of aspirin given in regular and enteric coated formulations for a 2-week period is sufficient to inhibit platelet function in men and women , a r and omized , double-blind , placebo-controlled trial was conducted among 22 healthy volunteers evaluating the effects of these preparations on platelet aggregation induced by arachidonic acid , adenosine diphosphate , and epinephrine , and on plasma concentrations of thromboxane and prostacyclin . Results During the active aspirin phase of the study , all subjects demonstrated a clinical anti-platelet effect as evidence d by failure of the platelets to aggregate in the presence of at least one platelet agonist , and mean thromboxane and prostacyclin levels decreased to 7.5 and 15.6 % of baseline , respectively ( both P < 0.001 ) . After cessation of active aspirin , all subjects had full recovery of platelet function as well as thromboxane and prostacyclin production . There were virtually no differences between regular and enteric coated formulations , or between men and women . Conclusion These data indicate that an alternate day regimen of 100 mg aspirin given in either regular or enteric coated formulation is adequate to achieve functional platelet inhibition . The clinical efficacy of this dose and formulation of aspirin is being tested in the ongoing Women 's Health Study , a r and omized , double-blind , placebo-controlled trial of 40 000 female health professionals design ed in part to assess the benefits and risks of 100 mg alternate day aspirin in the primary prevention of cardiovascular disease Since platelet cyclo-oxygenase is much more sensitive to inactivation by aspirin than is the enzyme in the arterial wall and low doses of aspirin may prevent thrombosis by blocking thromboxane synthesis , we conducted a r and omized , double-blind trial of aspirin ( 160 mg per day ) vs. placebo in 44 patients on chronic hemodialysis . The study was continued until there were 24 patients with thrombi and both groups had been under observation for a mean of nearly five months . Thrombi occurred in 18 of 25 ( 72 per cent ) of patients given placebo and 16 of 19 ( 32 per cent ) of those given aspirin ( P less than 0.01 ) . The incidence of thrombosis was reduced from 0.46 thrombi per patient month in the placebo group to 0.16 thrombi per patient month in the aspirin group ( p less than 0.005 ) . A dose of 160 mg of aspirin per day is an effective , nontoxic antithrombotic regimen in patients on hemodialysis Essential thrombocythemia ( ET ) is characterized by enhanced platelet generation and thrombotic complications . Once-daily low-dose aspirin incompletely inhibits platelet thromboxane A(2 ) ( TXA(2 ) ) in the majority of ET patients . In the present study , we investigated the determinants of aspirin-insensitive platelet TXA(2 ) bio synthesis and whether it could be further suppressed by changing the aspirin dose , formulation , or dosing interval . In 41 aspirin-treated ET patients , the immature platelet count predicted serum TXB(2 ) independently of platelet count , age , JAK-2 V617F mutation , or cytoreduction ( β = 3.53 , P = .001 ) . Twenty-one aspirin-treated patients with serum TXB(2 ) ≥ 4 ng/mL at 24 hours after dosing were r and omized to the following 7-day regimens in a crossover design : enteric-coated aspirin 100 mg twice daily , enteric-coated aspirin 200 mg once daily , or plain aspirin 100 mg once daily . A twice-daily regimen caused a further 88 % median ( IQR , 78%-92 % , P < .001 ) TXB(2 ) reduction and normalized the functional platelet response  to  aspirin , as assessed by urinary 11-dehydro-TXB(2 ) excretion and the VerifyNow Aspirin assay . Doubling the aspirin dose reduced serum TXB(2 ) only partially by 39 % median ( IQR , 29%-54 % , P < .05 ) . We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorter-lasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1 , and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose 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 Aspirin interferes with platelet aggregation by inhibiting the metabolism of arachidonic acid to thromboxane A2 . Although both high- and low-dose aspirin therapies are effective for secondary prophylaxis in patients with atherosclerotic vascular disease , the acute response to low-dose aspirin therapy is controversial . Eighteen volunteer subjects ingested 81 , 162 , or 324 mg of aspirin in a longitudinal crossover study design . Initial doses were r and omly assigned and dosing intervals were separated by 2 weeks . Platelet aggregation in response to 0.9 mM arachidonic acid was measured at baseline , 15 , 30 , 60 , and 90 minutes after ingestion . Thromboxane B2 production was assayed on simultaneously obtained sample s after stimulation with arachidonic acid . The median inhibition of aggregation was 97 % , 97 % , and 97 % 15 minutes after ingestion of 81 , 162 , and 324 mg , respectively . Four subjects had < 20 % inhibition 15 minutes after ingesting 81 mg , but all 4 had > 90 % inhibition after 30 minutes . Thromboxane B2 production declined by > 93 % in all subjects at each dose . There was no difference between doses in inhibition of thromboxane B2 production Background and Purpose Dual antiplatelet therapy ( DAT ) with clopidogrel and aspirin has been shown to confer greater protection against early neurological deterioration ( END ) and early recurrent ischemic stroke ( ERIS ) than aspirin alone in patients who have experienced an acute ischemic stroke . However , few studies have compared the effects of anticoagulation therapy with low-molecular-weight heparin ( LMWH ) , DAT , and aspirin . Methods Patients with acute ischemic stroke ( n=1,467 ) were r and omized to therapy groups receiving aspirin ( 200 mg daily for 14 days , followed by 100 mg daily for 6 months ) , DAT ( 200 mg of aspirin and 75 mg of clopidogrel daily for 14 days , then 100 mg of aspirin daily for 6 months ) , or LMWH ( 4,000 antifactor Xa IU of enoxaparin in 0.4 mL subcutaneously twice daily for 14 days , followed by 100 mg of aspirin daily for 6 months ) . The effects of these treatment strategies on the incidence of END , ERIS , and deep-vein thrombosis ( DVT ) were observed for 10 - 14 days after treatment , and their impacts on a good outcome were evaluated at 6 months . Results The DAT and LMWH were associated with a more significant reduction of END and ERIS within 14 days compared with aspirin-alone therapy . In addition , LMWH was associated with a significantly lower incidence of DVT within 14 days . At 6 months , DAT or LMWH improved the outcome among patients aged > 70 years and those with symptomatic stenosis in the posterior circulation or basilar artery compared with aspirin . Conclusions LMWH or DAT may be more effective than aspirin alone for reducing the incidence of END and ERIS within 14 days , and is associated with improved outcomes in elderly patients and those with stenosis in the posterior circulation or basilar artery at 6 months poststroke OBJECTIVES The goal of this study was to determine whether there is a relationship between aspirin dose and the potent antiplatelet agent prasugrel in the TRITON-TIMI 38 ( Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infa rct ion 38 ) study . BACKGROUND Optimal aspirin dosing after acute coronary syndromes remains uncertain . Previous studies have raised questions regarding an interaction between high-dose aspirin and the potent antiplatelet agent ticagrelor . METHODS In TRITON-TIMI 38 , we classified 12,674 patients into low-dose ( < 150 mg ) or high-dose ( ≥150 mg ) aspirin groups based on discharge dose . We identified independent correlates of dose selection and studied the impact of aspirin dose on the clinical effects of prasugrel . RESULTS There was significant geographical variation in aspirin dosing , with North American patients receiving high-dose aspirin more frequently than other countries ( 66 % vs. 28 % ; p < 0.001 ) . Clinical factors correlating with high-dose aspirin included previous percutaneous coronary intervention and use of aspirin before r and omization . Characteristics associated with the use of low-dose aspirin included age ≥75 years , white race , and use of bivalirudin or a glycoprotein IIb/IIIa inhibitor during coronary intervention . Regardless of low- or high-dose aspirin use , prasugrel had lower rates of the primary efficacy endpoint ( cardiovascular death , myocardial infa rct ion , or stroke [ CVD/MI/stroke ] ) ( hazard ratio [HR]CVD/MI/stroke = 0.78 [ 95 % confidence interval ( CI ) 0.64 to 0.95 ] and HRCVD/MI/stroke = 0.87 [ 95 % CI 0.69 to 1.10 ] , respectively ; p value for interaction = 0.48 ) and higher rates of the primary safety endpoint ( HR TIMI major bleeding = 1.40 [ 95 % CI 0.81 to 2.42 ] and TIMImajor bleeding = 1.30 [ 95 % CI 0.63 to 2.68 ] , respectively ; p value for interaction = 0.84 ) compared with clopidogrel . CONCLUSIONS In TRITON-TIMI 38 , the safety and efficacy outcomes of prasugrel compared with those of clopidogrel were directionally consistent regardless of aspirin dose , although only the primary efficacy endpoint achieved statistical significance . There was no clinical ly meaningful interaction of aspirin with prasugrel , suggesting that previous observations with potent antiplatelet agents indicating differential results are not universal . ( A Comparison of Prasugrel [ CS-747 ] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention ; NCT00097591 ) OBJECTIVES This study was design ed to determine if aspirin resistance is associated with clinical events . BACKGROUND Aspirin resistance , defined by platelet function testing and presumed clinical unresponsiveness to aspirin , has been previously reported by our group and others . However , little information exists linking the laboratory documentation of aspirin resistance and long-term clinical events . METHODS We prospect ively enrolled 326 stable cardiovascular patients from 1997 to 1999 on aspirin ( 325 mg/day for > or = 7 days ) and no other antiplatelet agents .  We tested for aspirin sensitivity by optical platelet aggregation using adenosine diphosphate ( ADP ) and arachidonic acid ( AA ) . The primary outcome was the composite of death , myocardial infa rct ion ( MI ) , or cerebrovascular accident ( CVA ) . Mean follow-up was 679 + /- 185 days . Aspirin resistance was defined as a mean aggregation of > or = 70 % with 10 microM ADP and > or = 20 % with 0.5 mg/ml AA . RESULTS Of the patients studied , 17 ( 5.2 % ) were aspirin resistant and 309 ( 94.8 % ) were not aspirin resistant . During follow-up , aspirin resistance was associated with an increased risk of death , MI , or CVA compared with patients who were aspirin sensitive ( 24 % vs. 10 % , hazard ratio [ HR ] 3.12 , 95 % confidence interval [ CI ] 1.10 to 8.90 , p = 0.03 ) . Stratified multivariate analyses identified platelet count , age , heart failure , and aspirin resistance to be independently associated with major adverse long-term outcomes ( HR for aspirin resistance 4.14 , 95 % CI 1.42 to 12.06 , p = 0.009 ) . CONCLUSIONS This study demonstrates the natural history of aspirin resistance in a stable population , documenting a greater than threefold increase in the risk of major adverse events associated with aspirin resistance BACKGROUND Acute nondisabling cerebrovascular events are common and often portend a disabling stroke . Aspirin is the only antiplatelet agent to have been studied in patients presenting acutely with a cerebrovascular event , but the effect is modest and is reduced by a small increased risk of intracerebral hemorrhage . Treatment with the combination of clopidogrel and aspirin might be beneficial when taken soon after a transient ischemic attack ( TIA ) or minor stroke . The CHANCE trial is a r and omized , double-blind , multicenter , placebo-controlled trial to test an aggressive antiplatelet regimen in acute minor stroke or TIA . DESIGN The study will r and omize 5,100 Chinese patients with acute TIA or minor stroke to receive a 3-month regimen of clopidogrel initiated with a loading dose of 300 mg followed by 75 mg/d , combined with aspirin 75 mg/d during the first 21 days , or a 3-month regimen of aspirin 75 mg/d alone . The primary efficacy end point is percentage of patients with any stroke ( ischemic or hemorrhage ) at 3 months . Study visits will be performed on the day of r and omization , at day 21 , and at day 90 . SUMMARY CHANCE will determine whether clopidogrel combined with aspirin can prevent more strokes after acute minor stroke or TIA compared with aspirin alone-with an acceptable risk profile Dual antiplatelet therapy ( DAPT ) with clopidogrel and aspirin is a widely accepted strategy in patients undergoing transcatheter aortic valve implantation ( TAVI ) , but this approach is not evidence based . The goal of the present study was to determine whether DAPT in patients undergoing TAVI is associated with improved outcomes compared to aspirin alone . From May 2009 to August 2010 , consecutive patients were r and omized to receive a 300-mg loading dose of clopidogrel on the day before TAVI followed by a 3-month maintenance daily dose of 75 mg plus aspirin 100 mg lifelong ( DAPT group ) or aspirin 100 mg alone ( ASA group ) . The primary end point was the composite of major adverse cardiac and cerebrovascular events , defined as death from any cause , myocardial infa rct ion , major stroke , urgent or emergency conversion to surgery , or life-threatening bleeding . The cumulative incidence of major adverse cardiac and cerebrovascular events at 30 days and 6 months was 14 % and 16 % , respectively . No significant differences between the DAPT and ASA groups were noted at both 30 days ( 13 % vs 15 % , p = 0.71 ) and 6 months ( 18 % vs 15 % ; p = 0.85 ) . In conclusion , the strategy of adding clopidogrel to aspirin for 3 months after TAVI was not found to be superior to aspirin alone . These results must be confirmed in a larger r and omized trial Background and Purpose — Incomplete platelet inhibition by aspirin ( aspirin resistance ) may be a reason for stroke recurrence in some patients . 11-Dehydrothromboxane B2 ( 11-DTB2 ) is a stable thromboxane A2 metabolite that reflects in vivo platelet activation . This pilot study was intended to evaluate the reproducibility of urinary 11-DTB2 over time and to look for evidence of aspirin resistance . Methods — All subjects were screened for the African American Antiplatelet Stroke Prevention Study ( AAASPS ) 7 to 90 days after noncardioembolic cerebral infa rct ion . Of 83 subjects with at least 1 urine sample , 52 were enrolled in AAASPS ( r and omized to blinded treatment with aspirin 650 mg/d or ticlopidine 500 mg/d ) , and 31 were enrolled in an open-label antiplatelet therapy cohort .  Subjects were followed up for 2 years , with 11-DTB2 measurements scheduled at baseline and 6 , 12 , and 24 months . Vascular events were cerebral infa rct ion , myocardial infa rct ion , or vascular death . Results — Despite considerable individual up or down fluctuations , the median 11-DTB2 change did not significantly differ from zero in any of the subgroups . However , in 6 subjects with a 4-fold decrease in aspirin dose from 1300 to 325 or 81 mg/d , the 11-DTB2 level increased from 611 to 1881 pg/mg creatinine ( P = 0.06 ) . Vascular events occurred in 7 of 61 aspirin-treated subjects , and 11-DTB2 levels did not correlate with the events . Conclusions — Fluctuations in urinary 11-DTB2 after cerebral infa rct ion in blacks do not correlate with changes in aspirin doses , except perhaps when the dose changes by a factor of 4 or more . A larger study is needed to look further for aspirin resistance Should a neurologist recommend that an asymptomatic and healthy man take aspirin for prophylactic purpose s on a long-term basis ? This communication review s the issues engendered by this question . The results of two large studies have been published in the past 2 years in which healthy male physicians were r and omized for long-term prophylactic aspirin treatment or for assignment to a control cohort . The subjects were followed up for an average of 5 to 6 years . The Physicians ' Health Study ( PHS ) , 1 done in the United States ( aspirin , 325 mg every other day ) , showed a 44 % reduction in the risk of myocardial infa rct ion ( MI ) ; the P value was less than.00001 . The British study ( BS ) 2 showed no such benefit ( aspirin , 300 to 500 mg daily ) . Rates for deaths from all causes were somewhat lower in the aspirin cohorts in both studies , but the reductions were not statistically significant . In both studies , Background — Patients with type 2 diabetes mellitus ( T2DM ) have reduced aspirin-induced pharmacodynamic effects . This may be attributed to increased platelet turnover rates result ing in an increased proportion of non – aspirin-inhibited platelets during the daily dosing interval . The hypothesis of this study was that an increase in the frequency of drug administration [ twice daily ( bid ) versus once daily ( od ) ] may provide more effective platelet inhibition in T2DM patients . Methods and Results — T2DM patients with stable coronary artery disease were prospect ively recruited . Patients modified their aspirin regimen on a weekly basis according to the following scheme : 81 mg/od , 81 mg/bid , 162 mg/od , 162 mg/bid , and 325 mg/od . Pharmacodynamic assessment s included light-transmittance aggregometry after arachidonic acid , collagen and adenosine diphosphate stimuli ; VerifyNow-Aspirin assay ; and serum thromboxane B2 ( TXB2 ) levels .  Twenty patients were analyzed . All patients were sensitive and compliant to aspirin irrespective of dose , as assessed by arachidonic acid – induced aggregation . When aspirin was administered once daily , there was no significant effect on platelet reactivity by increasing the once-daily dosing using aspirin-sensitive assays ( collagen-induced aggregation and VerifyNow-Aspirin ) . An increase in aspirin dose by means of a second daily administration was associated with a significant reduction in platelet reactivity assessed by collagen-induced aggregation and VerifyNow-Aspirin between 81 mg/od and 81 mg/bid ( P<0.05 for both assays ) and between 81 mg/od and 162 mg/bid ( P<0.05 for both assays ) . There was no impact of aspirin dosing regimens on adenosine diphosphate – induced aggregation . A dose-dependent effect of aspirin was observed on serum TXB2 levels ( P=0.003 ) . Conclusions — Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable coronary artery disease , with a twice-daily , low-dose aspirin administration result ing in greater platelet inhibition than once-daily administration as assessed by aspirin-sensitive assays and a dose-dependent effect on serum TXB2 levels . The clinical implication s of a modified aspirin regimen tailored to T2DM patients warrant further investigation . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01201785
The available evidence , predominantly from secondary -prevention observational studies , supports that dosages greater than 75 to 81 mg/d do not enhance efficacy , whereas larger dosages are associated with an increased incidence of bleeding events , primarily related to gastrointestinal tract toxicity .
CONCLUSIONS Currently available clinical data do not support the routine , long-term use of aspirin dosages greater than 75 to 81 mg/d in the setting of cardiovascular disease prevention .
Higher dosages , which may be commonly prescribed , do not better prevent events but are associated with increased risks of gastrointestinal bleeding
CONTEXT More than 50 million US adults take aspirin regularly for long-term prevention of cardiovascular disease , typically either 81 mg/d or 325 mg/d .
Controversy remains regarding the most appropriate long-term daily dose .
OBJECTIVE To review the mechanism of action of aspirin and the clinical literature for relationships among  aspirin dosage , efficacy , and safety .
EVIDENCE SYNTHESIS Although pharmacodynamic data demonstrate that long-term aspirin dosages as low as 30 mg/d are adequate to fully inhibit platelet thromboxane production , dosages as high as 1300 mg/d are approved for use .