Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting Dose Effects of Aspirin on Gastric Prostaglandins and Stomach Mucosal Injury Effect of Low‐Dose Aspirin on Fetal and Maternal Generation of Thromboxane by Platelets in Women at Risk for Pregnancy‐Induced Hypertension Effects of low-dose aspirin on in vitro platelet aggregation in the early minutes after ingestion in normal subjects. Aspirin therapy: optimized platelet inhibition with different loading and maintenance doses. Relationship of low-dose aspirin to GI injury and occult bleeding: a pilot study. Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease Eicosanoid biosynthesis in patients with stable angina: beneficial effects of very low dose aspirin. 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 Selection of aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory 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. Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet Glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial. Heterogeneity in platelet cyclooxygenase inhibition by aspirin in coronary artery disease. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. Association of Cyclooxygenase-1–Dependent and –Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization Low‐Dose Aspirin in Pregnancy Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. Biological efficacy of low against medium dose aspirin regimen after coronary surgery: analysis of platelet function. Low-dose aspirin increases aspirin resistance in patients with coronary artery disease. A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. Comparison of effects of high-dose and low-dose aspirin on restenosis after femoropopliteal percutaneous transluminal angioplasty. Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications. The Effect of Aspirin Dosing on Platelet Function in Diabetic and Nondiabetic Patients
Context The optimal aspirin dose for prevention of cardiovascular events is unknown . Contribution This post hoc analysis of CHARISMA trial data suggests no overall differences in efficacy or safety by aspirin dose . However , in the subgroup of patients r and omly assigned to clopidogrel , there was a hint of reduced efficacy and increased harm with higher doses . Caution Patients were not r and omly assigned to aspirin dose . Implication Lower aspirin doses ( 75 to 81 mg/d ) may optimize efficacy and safety for patients requiring aspirin for long-term prevention , especially those taking clopidogrel .  The Editors Aspirin is the most widely used drug worldwide for the prevention of thrombotic cardiovascular events . Of note , the doses of aspirin used most often clinical ly or recommended in guidelines are based not on the results of trials design ed to identify the most efficacious or safest dose , but on a combination of historical precedents and trials in which specific doses of aspirin were m and ated by protocol . This practice has led to a wide range in aspirin doses ( 75 to 325 mg/d ) recommended by the U.S. Food and Drug Administration ( 1 ) for the management of cardiovascular disease in various population s. Although as little as 30 mg of aspirin daily is needed to fully inhibit platelet thromboxane production ( 2 ) , doses more than 10 times higher than this are routinely used in long-term prevention of cardiovascular disease . Because aspirin has been used clinical ly for more than a century and is a mainstay of therapy for patients who have or are at risk for atherosclerotic disease and other common ailments , its risks are often underappreciated . However , given that more than one third of U.S. adults are estimated to take aspirin daily for cardiovascular disease ( 3 ) , even a very small incidence of hemorrhagic complications places a large number of people at risk . Consistent with this is a recent analysis of hospitalizations for adverse drug effects that found aspirin to be one of the most common causal agents ( 4 ) . The gastrointestinal tract is the leading source of bleeding events in  aspirin-treated  patients because of inhibition of gastroprotective prostacyclins , with an excess risk for upper gastrointestinal complications of 5 cases per 1000 aspirin users per year ( 5 ) . Prospect i ve evaluation of  aspirin-treated patients with coronary artery disease identified an incidence of upper gastrointestinal bleeding of 1.5 % per year , with substantial associated morbidity ( 6 ) . Because inhibition of gastric prostacyclin is dose-dependent and not maximal until a daily dose of about 1300 mg is reached ( 4 ) , minimizing the dose of aspirin to that needed to fully inhibit platelet thromboxane production would probably offer the greatest potential benefit with the lowest possible risk . In several observational studies of large prospect i ve trials , lower doses of aspirin ( < 162 mg/d ) have been associated with the lowest incidence of thrombotic events ( 7 , 8) and a trend toward fewer bleeding events ( 8) . These favorable trends in efficacy and safety were confirmed in the CURE ( Clopidogrel in Unstable angina to prevent Recurrent Events ) trial ( 9 ) of dual antiplatelet therapy with clopidogrel plus aspirin versus placebo plus aspirin . On the basis of these results , the design of the CHARISMA ( Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ) trial ( 10 ) , which r and omly assigned 15603 patients at high risk for atherothrombotic events to clopidogrel or placebo in conjunction with aspirin , m and ated a daily aspirin dose of 75 to 162 mg . We performed a post hoc analysis of associations between investigator-determined daily aspirin dose and thrombotic and hemorrhagic outcomes in the prospect i ve CHARISMA trial . Methods The design , methods , and primary results of the CHARISMA study are reported elsewhere ( 10 ) . In brief , CHARISMA was a multicenter , double-blind , r and omized , placebo-controlled trial of long-term clopidogrel ( 75 mg/d ) treatment versus placebo in patients 45 years or older who had established atherosclerotic disease or were asymptomatic but at high risk because of a combination of risk factors . All patients also received low-dose aspirin therapy , which was limited by protocol to between 75 and 162 mg/d . Patients were excluded if they had an established indication for clopidogrel therapy , such as a recent acute coronary syndrome or stent implantation . Clinical follow-up was done at 1 , 3 , and 6 months and every 6 months thereafter until the end of the trial . The actual dose of aspirin being taken was confirmed at each evaluation . The ethics committee at each of the 768 participating hospitals worldwide , as well as the appropriate national ethics committee for each of the 32 participating countries , review ed and approved the study protocol . All patients provided written informed consent before enrollment . The primary efficacy end point was the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . The primary safety end point was severe or life-threatening bleeding according to the GUSTO-I ( Global Utilization of Streptokinase and TPA for Occluded coronary arteries ) criteria ( 11 ) : intracerebral bleeding or bleeding result ing in substantial hemodynamic compromise requiring treatment . A secondary safety end point was the combined incidence of severe or life-threatening bleeding or moderate bleeding by the GUSTO-I criteria , with moderate defined as bleeding requiring transfusion but not result ing in hemodynamic compromise ( 11 ) . Of note , patients believed to be at high risk for bleeding were excluded from enrollment .  Aspirin dose was not r and omized ; rather , it was selected at the discretion of the treating physician . We prospect ively divided patients into 3 major groups according to clear demarcations in aspirin dose at baseline : less than 100 mg/d , represented almost entirely by doses of either 75 or 81 mg/d ; 100 mg/d ; and greater than 100 mg/d , represented by either 150 or 162 mg/d . We evaluated the relative efficacy and safety of the different doses of aspirin among all patients , and we evaluated the efficacy and safety end points between the treatment ( clopidogrel ) versus placebo groups by aspirin dose category . Statistical Analysis We performed all data analyses on the intention-to-treat population . We performed hypothesis tests by using 2-sided tests at the 5 % significance level . Baseline characteristics were compared by using chi-square tests for discrete variables and t tests for continuous variables . We calculated cumulative KaplanMeier estimates of the event rates and assessed differences in the unadjusted rates of primary efficacy and safety end points across the aspirin groups by using a 2-sided log-rank test . We used log-rank weights to compute a test for trend across aspirin dose categories . We estimated the treatment effect , measured by the hazard ratio and its 95 % CI , by using the Cox proportional hazards model . Multivariable modeling was performed to determine whether aspirin dose was independently associated with the primary efficacy and safety outcomes after controlling for potentially confounding factors . Because patients could have had more than 1 efficacy or safety event , we defined the time to the primary efficacy end point as the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . We defined the time to the primary safety end point as the first occurrence of severe or life-threatening bleeding according to the GUSTO-I criteria ( 11 ) . We selected variables for inclusion in the models on the basis of differences in baseline characteristics among patients in the 3 aspirin dose categories or their clinical relevance to the outcomes . Covariates included in the multivariable model for the primary efficacy end point were the continuous variables of age , weight , and systolic blood pressure and the categorical variables of sex ; race or ethnicity ( white or Hispanic vs. other ) ; hypertension ; hypercholesterolemia ; history of congestive heart failure ; previous myocardial infa rct ion ; previous stroke ; previous transient ischemic attack ; diabetes mellitus ; atrial fibrillation ; peripheral arterial disease ; diabetic nephropathy ; current smoking ; primary ( vs. secondary ) prevention and past use of statins , nitrates , and antiplatelet agents other than aspirin . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by aspirin dose category . Adjustment variables in the multivariable model for the primary safety end point ( GUSTO-I severe or life-threatening bleeding ) included age and weight as continuous variables and the categorical variables of stable angina with multivessel disease , sex , race or ethnicity ( white or Hispanic vs. other ) , history of congestive heart failure , previous myocardial infa rct ion , previous stroke , previous transient ischemic attack , diabetes mellitus , atrial fibrillation , peripheral arterial disease , diabetic nephropathy , hypertension , hypercholesterolemia , primary prevention ( vs. secondary ) , and current smoking . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by daily aspirin dose category . To adjust for geographical region without estimating its effect , we used region ( categorized as United States , Canada , Western Europe , Eastern Europe , Latin America , Asia and Australia , or Africa ) as a stratification variable in models for both end points . We assessed the interaction of  aspirin dose and r and omized treatment in both models . We calculated and tested the difference between the maximum likelihood ratios with and without 2 interaction terms ( r and omized treatment assignment by daily aspirin dose of 100 mg and greater than 100 mg ) . We assessed proportional hazards by multiplying each covariate by the log of the time to the event . A Wald test was performed to test the linear hypotheses of the regression coefficients . The proportional Once-daily ( od ) , low-dose aspirin ( 75–100 mg ) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia ( ET ) . This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera , with the assumption of similar aspirin pharmacodynamics in the two setting s. However , the pharmacodynamics of low-dose aspirin is impaired in ET , reflecting accelerated renewal of platelet cyclooxygenase (COX)-1 . ARES is a parallel-arm , placebo-controlled , r and omized , dose-finding , phase II trial enrolling 300 ET patients to address two main questions . First , whether twice or three times 100 mg aspirin daily dosing is superior to the st and ard od regimen in inhibiting platelet thromboxane (TX)A2 production , without inhibiting vascular prostacyclin bio synthesis . Second , whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen . Considering that the primary study end point is serum TXB2 , a surrogate biomarker of clinical efficacy , a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented . The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB2 as a reliable end point for dose-finding studies of novel aspirin regimens Aspirin is almost certainly the most widely used drug in the world . It is used both therapeutically ( to reduce pain , inflammation , and fever ) and prophylactically ( to prevent thrombotic events ) . Although prophylactic , antithrombotic doses of aspirin are generally lower than therapeutic doses , epidemiologic studies suggest that such doses may still be associated with gastrointestinal damage [ 1 - 3 ] . In a long-term , placebo-controlled study evaluating aspirin for secondary prevention of myocardial infa rct ion , a daily dose of 1000 mg increased the risk for hospitalization for gastric and duodenal ulcers by about eightfold [ 1 ] . In another long-term , placebo-controlled study evaluating aspirin for stroke prevention in patients with transient ischemic attacks , the rate of hospitalization for serious gastrointestinal bleeding was increased approximately threefold with 1200 mg of aspirin per day and twofold with just 300 mg of aspirin per day [ 2 ] . In another long-term study for primary prevention of cardiovascular diseases , an aspirin dose of 325 mg given every other day was associated with a significantly greater risk for duodenal ulcer when compared with placebo [ 3 ] . Few experimental data exist on the risk for gastroduodenal mucosal injury as a function of aspirin dose , and it is not known whether any clinical ly used dose of aspirin is free of risk for gastroduodenal mucosal damage . In a recent endoscopic study of patients with coronary artery disease , most of whom were receiving only 100 mg of aspirin per day , the prevalence of gastric erosions was higher than the prevalence of erosions in a historical control group [ 4 ] . The literature contains little information on the relation between aspirin dosage and suppression of gastroduodenal mucosal prostagl and in synthesis in humans . Because suppression of gastroduodenal mucosal prostagl and in synthesis appears to be one of the important mechanisms for mucosal damage by aspirin [ 5 , 6 ] , it would be useful to determine the threshold dose for gastroduodenal mucosal prostagl and in inhibition in humans because aspirin doses below this threshold may not damage the gastroduodenal mucosa . Our goal was to determine the effects of a wide range of doses of aspirin ( 3 mg/d to 2600 mg/d ) on gastric juice prostagl and ins ( PGE2 and PGF2 ) and on stomach mucosal injury as reflected by gastric juice hemoglobin and DNA , both of which are sensitive indicators of mucosal injury [ 7 , 8 ] . Effects of various doses of aspirin were also related to their effects on gastric acid secretion and serum thromboxane B2 . Methods Healthy volunteers between the ages of 18 and 75 years were solicited through advertisement . All respondents had a screening history , physical examination , complete blood count , and serum electrolyte , creatinine , bilirubin , and liver chemistry tests . Volunteers were excluded for heartburn ; abdominal pain ; indigestion ; bloating ; fullness ; nausea and vomiting ; use ( within the previous 2 weeks ) of aspirin , nonsteroidal anti-inflammatory drugs , glucocorticoids , histamine-2-receptor antagonists , sucralfate , misoprostol , omeprazole , antacids , or Pepto-Bismol ( Procter and Gamble , Cincinnati , Ohio ) ; history of allergy to aspirin or topical tetracaine ; a positive urine pregnancy test ; history of gastric surgery , peptic ulcer , or other gastrointestinal disease ; history of liver disease ( including currently elevated liver chemistry tests ) ; or history or presence of anemia , thrombocytopenia , leukopenia , gout , coagulation disorder , or renal insufficiency . Sixteen people ( 5 men and 11 women ) met all entry criteria and gave written consent to participate as paid volunteers . Use of any medication other than study medication was not allowed during the study . The study was approved by the Human Studies Subcommittee at the Department of Veterans Affairs Medical Center , Dallas , Texas . Part 1 Ten volunteers ( four men and six women ; mean age , 44.2 years ; range , 19 to 73 years ) were enrolled in part 1 of the study . One man was excluded for noncompliance . On 4 separate days at least 1 week apart , each of the other nine participants received placebo ( calcium sulfate , 222 mg ; cellulose , 97 mg ) ; aspirin , 81 mg ( Bayer Children 's Aspirin , Glenbrook Laboratories ; New York , New York ) ; aspirin , 325 mg ( one tablet ) ; or aspirin , 650 mg ( two 325-mg tablets ) . Medication was taken with each of three meals and at bedtime on the day before the study and at 0700 h on the study day . During the course of four visits , each of the nine volunteers took each of the four drug regimens in r and om order . Medications were dispensed by a research pharmacist so that the investigators were blinded to the study regimens . Although the medications differed in appearance , volunteers were blinded to exact ingredients of the medications and were instructed to refrain from discussing their study regimens with the investigators and technical assistants . We used the dosing schedule of the highest dose of aspirin ( 650 mg four times a day ) in a previous study , which result ed in significant inhibition of gastric mucosal PGE2 and PGF2 concentrations [ 9 ] . Each volunteer was instructed to report to the research laboratory on the study day after an overnight fast . At 0800 h ( 1 hour after the fifth and final dose of medication ) , a venous blood sample was taken for determination of serum salicylate concentration . Then , a nasogastric tube was positioned fluoroscopically in the dependent portion of the gastric antrum . Volunteers were trained not to swallow their saliva and to collect saliva through dental suction catheters . Residual gastric secretion was aspirated with the volunteer in the supine position and the fluid was discarded . Beginning at 0830 h , gastric juice was collected by intermittent suction pump aspiration , and the sample s collected were divided into aliquots and placed in separate containers every 15 minutes for the next 2 hours . In our laboratory , typical recovery of gastric juice with a nasogastric tube positioned fluoroscopically is greater than 90 % [ 10 ] . Part 2 Eleven volunteers ( three men and eight women ; mean age , 45.2 years ; range , 25 to 73 years ) were enrolled in part 2 of the study . Two men were excluded for noncompliance . Four of the remaining nine volunteers ( one man and three women ) had participated in part 1 of the study . On five separate occasions at least 14 days apart , each volunteer received placebo ( calcium sulfate , 222 mg ; cellulose , 97 mg ) ; aspirin , 3 mg ; aspirin , 10 mg ; aspirin , 30 mg ; or aspirin , 81 mg for 8 days . Medications were prepared and packaged in identical green opaque gelatin capsules by the Pharmacy Service at Dallas Veterans Affairs Medical Center . Medications were dispensed by a research pharmacist so that the study was double-blinded . Volunteers were instructed to take the medication with breakfast for 7 days before the study and at 0600 h on the study day . During the course of five visits , each volunteer received each of the five drug regimens in r and om order . Each volunteer was instructed to report to the research laboratory after an overnight fast . At 0700 h ( 1 hour after the last dose of medication ) , venous blood sample s were drawn for serum salicylate and serum thromboxane B2 determinations . We chose to monitor serum thromboxane B2 concentrations in part 2 because data from part 1 suggested that aspirin doses of 324 mg/d or less would not result in any detectable serum salicylate level and because the serum thromboxane B2 level has been shown to be a clinical ly relevant and reliable marker of low-dose aspirin therapy [ 11 ] . After venipuncture , a nasogastric tube was positioned fluoroscopically in the gastric antrum , as described above . Beginning at 0730 h , gastric juice was collected by intermittent suction pump aspiration and sample s collected were divided into aliquots and placed in separate containers every 15 minutes for the next 60 minutes . We chose to do this study for 60 minutes because results from part 1 indicated that no substantial fluctuations in gastric juice prostagl and in , hemoglobin , and DNA , or gastric acid outputs occurred throughout the 2-hour study period . The aspirin dosing schedule was chosen based on the following observations : 1 ) Thirty mg of aspirin daily has recently been shown to be as effective as 283 mg daily in the prevention of cerebrovascular events in patients with a transient ischemic attack or minor stroke [ 12 ] ; 2 ) reduction of serum thromboxane B2 by low-dose aspirin is cumulative on repeated daily dosing and has been shown to reach a steady state after 7 days [ 13 ] ; and 3 ) serum thromboxane B2 generally returns to normal by 14 days after cessation of aspirin therapy [ 13 , 14 ] . Processing of Gastric Juice Sample s and Determination of Gastric Acid Output The volume of each 15-minute gastric juice sample was recorded to the nearest 0.2 mL , and indomethacin was added immediately to the sample after collection ( final indomethacin concentration , 50 M ) to prevent further prostagl and in synthesis . The pH of each sample was determined by glass electrode . Acidity was derived from the pH [ 15 ] and expressed as mmol/L. Acid output was calculated by multiplying volume by acidity , expressed as mmol/h . To stabilize prostagl and ins in the specimen , the sample was then titrated to pH 7.0 with 0.2-N NaOH and kept at 4 C. Sample s were processed the same day that they were collected and used in subsequent determinations of PGE2 , PGF2 , hemoglobin , and DNA concentrations . Determination of Gastric Juice PGE2 and PGF2 Output Extraction of prostagl and ins from gastric juice sample s was done according to the method of Peskar and colleagues [ 16 ] . Aliquots of gastric juice that had been titrated to pH 7.0 were homogenized and centrifuged . The result ant supernatant was titrated to pH 3.0 with acetic acid . The acidified supernatant was extracted twice with four volumes of ethyl acetate . The organic extracts were pooled and stored at 70C until radioimmunoassay . Before the assay , organic extracts were There is evidence that aspirin in low doses favorably influences the course of pregnancy-induced hypertension , but the mechanism , although assumed to involve suppression of the production of thromboxane by platelets , has not been established . We performed a r and omized study of the effect of the long-term daily administration of 60 mg of aspirin  ( n = 17 ) or placebo ( n = 16 ) on platelet thromboxane A2 and vascular prostacyclin in women at risk for pregnancy-induced hypertension . Low doses of aspirin were associated with a longer pregnancy and increased weight of newborns . Serum levels of thromboxane B2 , a stable product of thromboxane A2 , were almost completely ( greater than 90 percent ) inhibited by low doses of aspirin . The urinary excretion of immunoreactive thromboxane B2 was significantly reduced without changes in the level of 6-keto-prostagl and in F1 alpha , a product of prostacyclin . Mass spectrometric analysis showed that aspirin reduced the excretion of the 2,3-dinor-thromboxane B2 metabolite -- mainly of platelet origin -- by 81 percent and of thromboxane B2 , probably chiefly of renal origin , by 59 percent . The urinary excretion of 6-keto-prostagl and in F1 alpha and of its metabolite 2,3-dinor-6-keto-prostagl and in F1 alpha was not affected . Low doses of aspirin only partially ( 63 percent ) reduced neonatal serum thromboxane B2 . No hemorrhagic complications were observed in the newborns . Thus , in women at risk for pregnancy-induced hypertension , low doses of aspirin selectively suppressed maternal platelet thromboxane B2 while sparing vascular prostacyclin , but only partially suppressed neonatal platelet thromboxane B2 , allowing hemostatic competence in the fetus and newborn 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 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 BACKGROUND Low-dose aspirin is commonly used in patients with cardiovascular disease . However , little is known about the effect of aspirin on occult blood loss caused by gastrointestinal injury . Therefore , we studied endoscopic injury and fecal occult blood loss in patients ingesting different quantities of low-dose aspirin .  METHODS Forty healthy volunteers were enrolled in a r and omized , double-blind , prospect i ve , pilot endoscopic study . Each volunteer underwent 30 days of treatment with daily aspirin 30 mg , 81 mg , 325 mg , or placebo . Subjects completed fecal occult blood test cards before and at the end of treatment of two types : guaiac impregnated ( Hemoccult and Hemoccult SENSA ) and immunochemical ( HemeSelect and FlexSure OBT ) . Each volunteer underwent upper endoscopy at baseline and after completing 30 days of study medication . RESULTS Aspirin did not induce significant injury as determined by endoscopy when compared with placebo . Six of 30 volunteers taking aspirin developed erosions , whereas 1 of 10 subjects on placebo developed a new erosion ( p = 0.66 ) . Aspirin ( 325 mg ) was associated with a higher mean symptom score than the lower aspirin dosages and the placebo group ( p = 0.12 ) . Only one subject taking aspirin ( 325 mg ) had fecal occult blood on a single HemeSelect card . No subject had a positive fecal occult blood test with Hemoccult II , Hemoccult II SENSA , or FlexSure OBT cards . CONCLUSIONS Aspirin in dosages commonly used for cardiovascular prophylaxis does not generally cause significant gastric or duodenal mucosal endoscopic lesions . In the absence of frank ulceration , low-dose aspirin does not result in positive fecal occult blood tests . Low-dose aspirin should not interfere with fecal occult blood testing and probably should not be stopped during stool collection 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 OBJECTIVE We assessed the production of eicosanoids and the effects of very low dose aspirin in patients with stable angina under basal conditions and during rapid atrial pacing . BACKGROUND Platelet activation occurs in acute ischemic syndromes but is still controversial in stable angina . Very low dose aspirin is known to be platelet selective and can be used to test the hypothesis of the platelet origin of increased thromboxane production in stable angina . METHODS Urinary excretion of eicosanoids was measured in 42 patients , including 24 patients with and 18 patients without coronary artery disease . The effects of 50 mg/day of aspirin were measured at rest and during pacing-induced ischemia in 10 patients with stable angina and were compared with a similar group of patients not treated by aspirin . RESULTS Excretion of 11-dehydro-thromboxane B2 was 2.6 times higher in patients with stable angina than in healthy subjects ( mean [ + /- SEM ] 74.8 + /- 13.0 [ 24 patients ] vs. 29.0 + /- 5.4 [ 18 patients ] ng/mmol of creatinine , p < 0.01 ) . Urinary prostacyclin metabolite levels did not differ between the two groups . Treatment for 8 days with 50 mg/day of aspirin inhibited platelet cyclooxygenase , as reflected by the 97 % reduction of in vitro serum thromboxane production . This aspirin regimen normalized the level of urinary thromboxane metabolites in patients with angina ( 17.3 + /- 3.4 ng/mmol of creatinine [ 10 patients ] , p < 0.001 from baseline level before treatment ) and did not change prostacyclin metabolite levels . Atrial pacing in patients with angina not treated with aspirin caused lactate and thromboxane release into the coronary sinus . In patients with very low dose aspirin therapy , pacing did not cause thromboxane release despite inducing myocardial ischemia . However , fractional lactate extraction decreased less sharply in patients with than without aspirin therapy . CONCLUSIONS Thromboxane production is greatly increased in patients with stable angina . Very low dose aspirin administered to these patients reduces thromboxane synthesis to normal levels , preserves prostacyclin bio synthesis and prevents acute thromboxane release into the coronary circulation during pacing-induced ischemia . Our data suggest that platelets ( not monocytes/macrophages ) are activated in stable angina to produce thromboxane 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 BACKGROUND Aspirin desensitization followed by daily aspirin therapy is effective add-on treatment for patients with aspirin-exacerbated respiratory disease . Prior studies used 650 mg of aspirin twice daily , but studies at lower dosages were inconclusive . OBJECTIVE We sought to determine the optimal daily dosage of aspirin treatment . METHODS We studied 137 patients who had undergone successful aspirin desensitization and r and omized them into 2 groups , 650 mg twice daily versus 325 mg twice daily . After 1 month , patients either increased or decreased their dosage based on their symptom control and continued that dosage for the remainder of the year . RESULTS Patients taking either 650 mg twice daily or 325 mg twice daily showed significant improvements in number of sinus infections , sinus operations , and hospitalizations for asthma ( all P < .0001 ) . Anosmia , nasal/sinus symptoms , and asthma symptoms also improved in both groups ( all P < .03 ) . Systemic corticosteroid dosages decreased by 3- and 4-fold in the 325 mg twice daily and 650 mg twice daily groups , respectively . Of the 137 patients , 32 had adverse effects  from or discontinued  aspirin therapy : 14 ( 44 % ) of 32 from the group r and omized to taking 650 mg twice daily and 18 ( 56 % ) of 32 from the group r and omized to 325 mg twice daily . The most common adverse effect was dyspepsia . CONCLUSION Both dosages were efficacious , and side effects occurred in both groups at similar frequencies . Some patients initially taking 325 mg twice daily required an increase to 650 mg twice daily for optimal symptom control . CLINICAL IMPLICATION S We recommend that patients begin daily aspirin therapy with 650 mg twice daily and subsequently decrease to the lowest effective dosage ( usually 325 mg twice daily ) 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 Parenteral administration of platelet glycoprotein IIb/IIIa ( GP IIb/IIIa ) receptor blockers can reduce ischemic complications of coronary angioplasty . Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention . The pharmacodynamic efficacy , clinical safety , and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known . The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis ( ORBIT ) Trial is a multicenter , placebo-controlled , r and omized trial of xemilofiban , an oral platelet GP IIb/IIIa blocking agent , administered to patients after percutaneous coronary intervention . METHODS AND RESULTS After successful elective percutaneous coronary intervention , 549 patients were r and omized to receive either placebo or xemilofiban in a dose of 15 or 20 mg . Stented patients r and omized to placebo also received ticlopidine 250 mg orally BID for 4 weeks . Patients who received abciximab during the coronary intervention and who were r and omized to receive xemilofiban  were administered a reduced dosage ( 10 mg TID for 2 weeks ) followed by the r and omized maintenance dose of 15 or 20 mg BID for 2 more weeks . All patients received 325 mg aspirin PO QD . Ex vivo platelet aggregation in response to 20 micromol/L ADP and 4 microg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients . All patients were followed clinical ly for 90 days . Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy . Plasma levels of xemilofiban correlated with the degree of platelet inhibition . Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events . Although this study was not powered to evaluate differences in clinical outcomes , a trend ( P=0.04 ) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose ( 20 mg ) of xemilofiban studied . CONCLUSIONS Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy . The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study ( EXCITE trial ) currently in progress BACKGROUND Platelets , long believed to be incapable of de novo protein synthesis , may retain their ability to form the cyclooxygenase ( COX ) enzyme once it has been inactivated by aspirin . This may explain the inefficacy of the drug to induce sustained platelet inhibition in certain patients . We evaluated the stability of platelet inhibition following once-daily enteric-coated aspirin administration . METHODS Platelet responsiveness to aspirin was evaluated in 11 stable coronary artery disease patients on chronic aspirin therapy before and 1 , 3 , 8 , and 24h after observed ingestion of 80-mg enteric-coated aspirin . Inhibition of the COX pathway was measured pharmacologically through plasma thromboxane ( Tx ) B(2 ) levels , and functionally by light transmission aggregometry in response to arachidonic acid . COX-independent platelet activity was measured in response to adenosine diphosphate , epinephrine and collagen . RESULTS Plasma TxB(2 ) levels showed profound inhibition of TxA(2 ) formation , which was stable throughout 24h , in all but 1 subject . This subject had optimal response to aspirin ( inhibition of platelet TxA(2 ) production within 1h ) , but recovered the ability to synthesize TxA(2 ) within 24h of aspirin ingestion . Arachidonic acid-induced platelet aggregation closely mirrored TxB(2 ) formation in this patient , portraying a functional ability of the platelet to aggregate within 24h of aspirin ingestion . COX-independent platelet aggregation triggered TxA(2 ) production to a similar extent in all patients , likely through signal-dependent protein synthesis . CONCLUSIONS COX-dependent platelet activity is recovered in certain individuals within 24h of aspirin administration . Further research should consider increasing aspirin dosing frequency to twice daily , to allow sustained inhibition in such subjects CONTEXT Conventional nonsteroidal anti-inflammatory drugs ( NSAIDs ) are associated with a spectrum of toxic effects , notably gastrointestinal ( GI ) effects , because of inhibition of cyclooxygenase (COX)-1 . Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown . OBJECTIVE To determine whether celecoxib , a COX-2-specific inhibitor , is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs . DESIGN The Celecoxib Long-term Arthritis Safety Study ( CLASS ) , a double-blind , r and omized controlled trial conducted from September 1998 to March 2000 . SETTING Three hundred eighty-six clinical sites in the United States and Canada . PARTICIPANTS A total of 8059 patients ( > /=18 years old ) with osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) were enrolled in the study , and 7968 received at least 1 dose of study drug . A total of 4573 patients ( 57 % ) received treatment for 6 months . INTERVENTIONS Patients were r and omly assigned to receive celecoxib , 400 mg twice per day ( 2 and 4 times the maximum RA and OA dosages , respectively ; n = 3987 ) ; ibuprofen , 800 mg 3 times per day ( n = 1985 ) ; or diclofenac , 75 mg twice per day ( n = 1996 ) . Aspirin use for cardiovascular prophylaxis ( < /=325 mg/d ) was permitted . MAIN OUTCOME MEASURES Incidence of prospect ively defined symptomatic upper GI ulcers and ulcer complications ( bleeding , perforation , and obstruction ) and other adverse effects during the 6-month treatment period . RESULTS For all patients , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76 % vs 1.45 % ( P = .09 ) and 2 . 08 % vs 3.54 % ( P = .02 ) , respectively . For patients not taking aspirin  , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44 % vs 1.27 % ( P = .04 ) and 1.40 % vs 2.91 % ( P = .02 ) . For patients taking aspirin  , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01 % vs 2.12 % ( P = .92 ) and 4.70 % vs 6.00 % ( P = .49 ) . Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss , GI intolerance , hepatotoxicity , or renal toxicity . No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs , irrespective of aspirin use . CONCLUSIONS In this study , celecoxib , at dosages greater than those indicated clinical ly , was associated with a lower incidence of symptomatic ulcers and ulcer complications combined , as well as other clinical ly important toxic effects , compared with NSAIDs at st and ard dosages . The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly . JAMA . 2000;284:1247 - Background — Poor clinical outcome in  aspirin-treated patients has been termed aspirin resistance and may result from inadequate inhibition of platelet cyclooxygenase-1 ( COX-1 ) by aspirin . The objectives of this study were to determine prospect ively whether COX-1–dependent and other platelet function assays correlate with clinical outcomes in aspirin-treated patients . Methods and Results — Blood was collected before percutaneous coronary intervention from 700 consecutive aspirin-treated ( 81 or 325 mg for ≥3 days ) patients . Platelet function was tested by ( 1 ) serum thromboxane B2 ; ( 2 ) arachidonic acid – stimulated platelet surface P-selectin and activated glycoprotein IIb/IIIa and leukocyte – platelet aggregates ; and ( 3 ) platelet function analyzer (PFA)-100 collagen-epinephrine and collagen-ADP closure time ( CT ) . Adverse clinical outcomes of all-cause death , cardiovascular death , and major adverse cardiovascular events ( cardiovascular death , myocardial infa rct ion , hospitalization for revascularization , or acute coronary syndrome ) were assessed by telephone interview and /or medical record review . Clinical outcomes information was obtained at 24.8±0.3 months after platelet function testing . By univariate analysis , COX-1–dependent assays , including serum thromboxane B2 level , were not associated with adverse clinical outcomes , whereas the COX-1–independent assay , PFA-100 collagen-ADP CT < 65 seconds , was associated with major adverse cardiovascular events ( P=0.0149 ) . After adjustment for covariables ( including sex , aspirin dose , Thrombolysis in Myocardial Infa rct ion risk score , clopidogrel use ) , both serum thromboxane B2 > 3.1 ng/mL and PFA-100 collagen-ADP CT < 65 seconds were associated with major adverse cardiovascular events . In contrast , indirect measures of platelet COX-1 ( arachidonic acid – stimulated platelet markers , shortened PFA-100 collagen-epinephrine CT ) were not significantly associated with adverse clinical outcomes even after adjustment for covariables . Conclusions — In this prospect i ve study of 700 aspirin-treated patients presenting for angiographic evaluation of coronary artery disease , residual platelet COX-1 function measured by serum thromboxane B2 and COX-1–independent platelet function measured by PFA-100 collagen-ADP CT , but not indirect COX-1–dependent assays ( arachidonic acid – stimulated platelet markers , shortened PFA-100 collagen-epinephrine CT ) , correlate with subsequent major adverse cardiovascular events . This study suggests that multiple mechanisms , including but not confined to inadequate inhibition of COX-1 , are responsible for poor clinical outcomes in aspirin-treated patients , and therefore the term aspirin resistance is inappropriate In a prospect i ve study , we evaluated the effects of low-dose aspirin  on maternal and neonatal plasma 6-keto-prostagl and in ( PG ) F1α concentration , platelet aggregation , platelet thromboxane production , and neonatal transitional circulation .  Forty women , at a mean ( ± SD ) of 37 ± 2 weeks ' gestation , were r and omized to receive ( N = 10 each ) placebo or 20 , 60 , or 80 mg of aspirin per day until delivery . Maternal serum 6-keto-PGF1α levels were not affected by these doses of aspirin , whereas thromboxane B2 generated during clotting of maternal blood was decreased significantly by 60 and 80 mg of aspirin by 1 week of therapy . Maternal platelet thromboxane B2 production in response to adenosine diphosphate or collagen was reduced 98 % by the 80-mg dose after 1 week of aspirin therapy . The 60-mg dose reduced maternal platelet thromboxane B2 production in response to adenosine diphosphate ( 50 % decrease ) or collagen ( 60 % decrease ) after 1 week of treatment , a nonsignificant difference . After 2 weeks of treatment with 60 mg of aspirin , platelet thromboxane B2 production induced by both collagen and adenosine diphosphate was inhibited significantly ( P < .01 ) . Neonatal serum levels of 6-keto-PGF1α and thromboxane B2 were not affected by any doses of aspirin . Further , neonatal platelet aggregation in response to platelet stimulation by collagen and adenosine diphosphate was not inhibited . All neonates  had echocardiographic evidence of a patent ductus arteriosus , and noninvasive estimates of pulmonary arterial pressure were similar among the groups of infants . We conclude that 60–80 mg of aspirin per day in the third trimester of pregnancy selectively inhibits maternal platelet cyclooxygenase without affecting neonatal platelet aggregation or pulmonary circulation CONTEXT R and omized trials of short-term aspirin use for prevention of recurrent colorectal adenoma have provided compelling evidence of a causal relationship between aspirin and colorectal neoplasia . However , data on long-term risk of colorectal cancer according to dose , timing , or duration of therapy with aspirin and other nonsteroidal anti-inflammatory drugs ( NSAIDs ) remain limited . OBJECTIVE To examine the influence of aspirin and NSAIDs in prevention of colorectal cancer . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve cohort study of 82 911 women enrolled in the Nurses ' Health Study providing data on medication use biennially since 1980 and followed up through June 1 , 2000 . MAIN OUTCOME MEASURE Incident colorectal cancer . RESULTS Over a 20-year period , we documented 962 cases of colorectal cancer . Among women who regularly used aspirin ( > or = 2 st and ard [ 325-mg ] tablets per week ) , the multivariate relative risk ( RR ) for colorectal cancer was 0.77 ( 95 % confidence interval [ CI ] , 0.67 - 0.88 ) compared with nonregular users . However , significant risk reduction was not observed until more than 10 years of use ( P < or = .001 for trend ) . The benefit appeared related to dose : compared with women who reported no use , the multivariate RRs for cancer were 1.10 ( 95 % CI , 0.92 - 1.31 ) for women who used 0.5 to 1.5 st and ard aspirin tablets per week , 0.89 ( 95 % CI , 0.73 - 1.10 ) for 2 to 5 aspirin per week , 0.78 ( 95 % CI , 0.62 - 0.97 ) for 6 to 14 aspirin per week , and 0.68 ( 95 % CI , 0.49 - 0.95 ) for more than 14 aspirin per week ( P<.001 for trend ) . Notably , women who used more than 14 aspirin per week for longer than 10 years in the past had a multivariate RR for cancer of 0.47 ( 95 % CI , 0.31 - 0.71 ) . A similar dose-response relationship was found for nonaspirin NSAIDs ( P = .007 for trend ) . The incidence of reported major gastrointestinal bleeding events per 1000 person-years also appeared to be dose-related : 0.77 among women who denied any aspirin use ; 1.07 for 0.5 to 1.5 st and ard aspirin tablets per week ; 1.07 for 2 to 5 aspirin per week ; 1.40 for 6 to 14 aspirin per week ; and 1.57 for more than 14 aspirin per week . CONCLUSIONS Regular , long-term aspirin use reduces risk of colorectal cancer .  Nonaspirin NSAIDs appear to have a similar effect . However , a significant benefit of aspirin is not apparent until more than a decade of use , with maximal risk reduction at doses greater than 14 tablets per week . These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially higher than those recommended for prevention of cardiovascular disease , but the dose-related risk of gastrointestinal bleeding must also be considered The failure of aspirin to inhibit platelet function has been documented in patients undergoing coronary artery bypass graft ( CABG ) surgery , but the causes of " aspirin-resistance " remain uncertain . The aim of this study was to investigate the efficacy of aspirin in patients undergoing CABG surgery receiving either 100 mg or 325 mg of oral aspirin for 5-days . Platelet function was tested the day before surgery and on day + 1 and day + 5 , and evaluated by changes in collagen-induced thromboxane-A2 ( TxA2 ) release and platelet aggregation following stimulation with collagen , ADP and epinephrine . In all patients , baseline platelet aggregation was significantly inhibited by pre-incubation with in vitro aspirin ( 150 micromol/l ) , with a mean reduction in TxA2-release of > or=95.5 % ( 82.3,99.1 ) . After 5-days of oral aspirin , platelet aggregation was significantly inhibited , and was not further inhibited by in vitro aspirin . Oral aspirin was also associated with a > or=99.5 % ( 97.8 , 99.7 ) reduction in TxA2-release , and with the reversal of the second-phase of ADP-induced aggregation which is TxA2-dependent . In addition a single-dose of 325 mg aspirin on the first post-operative morning may have a greater inhibitory effect on collagen-induced aggregation than 100 mg aspirin . Western blot analysis provided no evidence for the presence of COX-2 in platelets , while the up-regulation of p38-MAPK following platelet-stimulation and surgery was seen . The inhibition of COX-2 ( NS398 ) or p38-MAPK ( SB203580 ) activity did not affect platelet aggregation and TxA2-release on day + 5 . In summary , there was no evidence for inherent or acquired aspirin-resistance in this surgical population , or for the involvement of either COX-2 or p38-MAPK 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 Epidemiologic evidence indicates that aspirin use is associated with reduced risks of colon cancer and possibly several other cancers , including prostate and breast cancers . Recent results from the Women 's Health Study r and omized trial indicate that long-term use of low-dose aspirin ( 100 mg every other day ) does not substantially reduce cancer risk . However , the potential effect of long-term daily use of higher doses of aspirin on cancer incidence remains uncertain . METHODS We examined associations between long-term daily use of adult-strength aspirin ( > or = 325 mg/day ) and both overall cancer incidence and incidence of 10 types of cancer among 69,810 men and 76,303 women participating in the Cancer Prevention Study II Nutrition Cohort , a relatively elderly population .  Aspirin use was reported at enrollment in 1992 - 1993 and up date d in 1997 , 1999 , and 2001 . Multivariable Cox proportional hazards regression was used to calculate rate ratios ( RRs ) . RESULTS During follow-up through June 2003 , 10,931 men and 7196 women were diagnosed with cancer . Long-term ( > or = 5 years ) daily use of adult-strength aspirin , compared with no use , was associated with lower overall cancer incidence in men ( multivariable-adjusted RR = 0.84 , 95 % confidence interval [ CI ] = 0.76 to 0.93 ) and non-statistically significantly lower overall cancer incidence in women ( multivariable-adjusted RR = 0.86 , 95 % CI = 0.73 to 1.03 ) . Overall cancer incidence per 100,000 person-years ( st and ardized to the age distributions of men and women in the study ) with long-term daily aspirin use and no aspirin use was 1858 and 2163 , respectively , among men and 1083 and 1169 , respectively , among women . Long-term daily aspirin use was associated with lower incidence of colorectal cancer ( RR = 0.68 , 95 % CI = 0.52 to 0.90 among men and women combined ) and prostate cancer ( RR = 0.81 , 95 % CI = 0.70 to 0.94 ) and a non-statistically significant lower risk of female breast cancer ( RR = 0.83 , 95 % CI = 0.63 to 1.10 ) . CONCLUSIONS Long-term daily use of adult-strength aspirin may be associated with modestly reduced overall cancer incidence in population s among whom colorectal , prostate , and breast cancers are common BACKGROUND Long-term treatment with aspirin is recommended in patients with large-vessel peripheral arterial disease since these patients have a high risk of death from cardiovascular causes . Recent studies have demonstrated the prophylactic effect of low-dose aspirin in reducing the risk of cardiovascular events . Since aspirin is also recommended for prevention of late recurrence after peripheral angioplasty , the present study was undertaken to compare the effects of high-dose ( 1000 mg/d ) and low-dose ( 100 mg/d ) aspirin on long-term patency after femoropopliteal angioplasty . METHODS AND RESULTS Two hundred sixteen patients treated successfully by percutaneous transluminal angioplasty for femoropopliteal lesions were r and omly allocated to therapy with either 1000 or 100 mg aspirin daily . The follow-up was 24 months . The long-term results were analyzed using the Kaplan-Meier method , and differences between curves of cumulative patency were determined with the Wilcoxon and log-rank statistics . Complete follow-up information ( patency after 24 months , restenosis , and death ) was obtained in 207 patients . During the 2-year follow-up period , 72 patients --36 in the high-dose and 36 in the low-dose aspirin group , respectively -- developed angiographically verified reobstruction within the recanalized segment . By intention-to-treat analysis , the cumulative patency rates at 24 months were 62.5 % in the high-dose and 62.6 % in the low-dose aspirin group ( Wilcoxon , P = .97 ; log-rank , P = .97 ) . The cumulative survival at 24 months of follow-up was 86.6 % in the high-dose and 87.7 % in the low-dose aspirin group . The number of patients discontinuing therapy was 30 in the high-dose and 11 in the low-dose aspirin group ( P < .01 ) . Fewer patients receiving 100 mg of aspirin discontinued therapy because of gastrointestinal symptoms ( 4 versus 20 ) . CONCLUSIONS The data indicate that 100 mg aspirin is no less effective in the prevention of restenosis after femoropopliteal PTA than a 1000-mg dose and has fewer side effects The efficacy of low-dose aspirin in type 2 diabetes mellitus ( T2DM ) has been question ed . We tested if twice daily dosing of aspirin would be more effective in T2DM , possibly due to increased platelet turnover . A r and omised cross-over study compared 75 mg aspirin OD , 75 mg BID and 320 mg OD ( ≥ 2 week treatment periods ) in 25 patients with T2DM and micro- or macrovascular complications . Platelet responses were examined by impedance aggregometry ( WBA ) and the IMPACT-R aspirin  test in whole blood , light transmittance aggregometry in platelet-rich plasma ( LTA ) , and urinary 11-dehydro-thromboxane B2 ( TxM ) . Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD ( 9.7 ± 4.5 vs. 12.6 ± 3.5 ohm ; p = 0.003 ) or to 320 mg OD ( 11.5 ± 4.2 Ohms ; p = 0.049 ) . WBA responses to collagen were similarly attenuated by BID or high dosing ( by 12 - 14 % ; p = 0.02 for both ) . The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD ( p = 0.049 ) , but not to 320 mg OD . AA-induced aggregation by LTA was < 6.5 % on all occasions , with no differences between aspirin dosages . TxM was reduced after 320 mg OD ( p = 0.002 ) , but not 75 mg BID ( p = 0.07 ) . Reticulated platelets were highly correlated with mean platelet volume ( MPV ; r2 = 0.74 , p<0.0001 ) . Both markers for platelet turnover were correlated with AA-induced WBA , but neither identified patients who benefited from BID dosing dependably . In conclusion , twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients . Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest 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
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 .