title: Sex differences in platelet reactivity and response to low-dose aspirin therapy. A randomized factorial trial of reperfusion strategies and aspirin dosing in acute myocardial infarction. The DUCCS-II Investigators. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes: Observations From the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin--analysis of gastrointestinal bleeding during the UK-TIA trial. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. Secondary prevention of ischemic stroke with low dose acetylsalicylic acid. Randomized, Double-Blind, Placebo-Controlled, International Trial of the Oral IIb/IIIa Antagonist Lotrafiban in Coronary and Cerebrovascular Disease Aspirin absorption rates and platelet inhibition times with 325-mg buffered aspirin tablets (chewed or swallowed intact) and with buffered aspirin solution. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product Comparison of effects of high-dose and low-dose aspirin on restenosis after femoropopliteal percutaneous transluminal angioplasty. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. Aspirin dose and six-month outcome after an acute coronary syndrome. 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 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. Effects of aspirin (325 mg/day) on serum high-sensitivity C-reactive protein, cytokines, and adhesion molecules in healthy volunteers. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial Two year Cottbus reinfarction study with 30 mg aspirin per day. Eicosanoid biosynthesis in patients with stable angina: beneficial effects of very low dose aspirin. Acetylsalicylic acid 100 mg and 1000 mg daily in acute myocardial infarction suspects: a placebo-controlled trial. Dose Effects of Aspirin on Gastric Prostaglandins and Stomach Mucosal Injury
abstract: CONTEXT Recent r and omized trials suggest that women may not accrue the same cardioprotective benefits as men do from low-dose aspirin therapy used in primary prevention . Failure of aspirin to suppress platelet aggregation in women is one hypothesized mechanism . OBJECTIVE To examine differential platelet reactivity to low-dose aspirin therapy by sex . DESIGN , SETTING , AND PARTICIPANTS A clinical trial of aspirin at 81 mg/d for 14 days was conducted in 571 men and 711 women . Baseline and post-aspirin therapy measures included platelet aggregation to arachidonic acid , adenosine diphosphate , epinephrine , and platelet function analyzer closure time . MAIN OUTCOME MEASURE Sex differences in cyclooxygenase 1 ( COX-1 ) direct and indirect platelet activation pathways before and after administration of aspirin . RESULTS In 10 of the 12 platelet agonist exposures , women 's platelets were significantly more reactive at baseline . However , after aspirin therapy , the percent aggregation to arachidonic acid ( the direct COX-1 pathway ) decreased more in women than in men ( P<.001 ) and demonstrated near total suppression of residual platelet reactivity in both men and women . In COX-1 indirect pathways , women experienced the same or more platelet inhibition than men in 8 of the 9 assays yet retained modestly greater platelet reactivity after aspirin therapy . In multivariable analysis , female sex significantly predicted aggregation to 2 muM and 10 muM of adenosine diphosphate ( P = .02 and < .001 , respectively ) and collagen at 5 mug/mL ( P<.001 ) independent of risk factors , age , race , menopausal status , and hormone therapy . CONCLUSIONS Women experienced the same or greater decreases in platelet reactivity after aspirin therapy , retaining modestly more platelet reactivity compared with men . However , most women achieved total suppression of aggregation in the direct COX-1 pathway , the putative mechanism for aspirin 's cardioprotection The focus of new research efforts to improve the morbidity and mortality associated with acute myocardial infa rct ion ( AMI ) has turned to adjuvant agents that show promise of improving outcomes following coronary thrombolysis . We enrolled 162 patients with AMI in a r and omized trial comparing front-loaded tissue-plasminogen activator ( t-PA ) plus weight-adjusted heparin with anisoylated plasminogen streptokinase activator complex ( APSAC ) without heparin as well as st and ard-dose ( 325 mg ) and low-dose ( 81 mg ) aspirin . The primary end point was an in-hospital morbidity profile ; secondary end points were clinical and angiographic potency and hemorrhagic events . Selected sites performed an electrocardiographic sub study to determine the time to 50 % ST-segment recovery and the time to steady state . Although the trial was terminated when the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I trial showed that t-PA had a significant mortality advantage over streptokinase , important trends were evident . Patients given t-PA and heparin were better anticoagulated ( p = 0.001 ) , yet AP-SAC-treated patients had more bleeding complications . The primary end point favored t-PA ( 25.4 % vs 31.3 % ) , and the secondary end points were similar in both groups . In the electrocardiographic sub study , the t-PA group achieved both 50 % ST-segment recovery and steady-state recovery sooner than the APSAC group . Patients taking low-dose aspirin  had lower in-hospital mortality and less recurrent ischemia but more strokes than the st and ard-dose aspirin group . Thus , this trial demonstrated trends favoring front-loaded t-PA with weight-adjusted heparin over APSAC without heparin in the treatment of AMI . The use of low-dose aspirin did not appear to impose a loss of protection from adverse events , nor did st and ard-dose aspirin increase serious bleeding Abstract Objective To ascertain the current burden of adverse drug reactions ( ADRs ) through a prospect i ve analysis of all admissions to hospital . Design Prospect i ve observational study . Setting Two large general hospitals in Merseyside , Engl and . Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission . Main outcome measures Prevalence of admissions due to an ADR , length of stay , avoidability , and outcome . Results There were 1225 admissions related to an ADR , giving a prevalence of 6.5 % , with the ADR directly leading to the admission in 80 % of cases . The median bed stay was eight days , accounting for 4 % of the hospital bed capacity . The projected annual cost of such admissions to the NHS is £ 466 m ( € 706 m , $ 847 m ) . The overall fatality was 0.15 % . Most reactions were either definitely or possibly avoidable . Drugs most commonly implicated in causing these admissions included low dose aspirin , diuretics , warfarin , and non-steroidal anti-inflammatory drugs other than aspirin , the most common reaction being gastrointestinal bleeding . Conclusion The burden of ADRs on the NHS is high , accounting for considerable morbidity , mortality , and extra costs . Although many of the implicated drugs have proved benefit , measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit : harm ratio of the drugs Background —We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome ( ACS ) . Methods and Results —In the Clopidogrel in Unstable angina to prevent Recurrent Events ( CURE ) trial , 12 562 patients with ACS using aspirin , 75 to 325 mg daily , were r and omized to clopidogrel or placebo for up to 1 year . In this analysis , patients were divided into the following 3 aspirin dose groups : ≤100 mg , 101 through 199 mg , and ≥200 mg . The combined incidence of cardiovascular death , myocardial infa rct ion , or stroke was reduced by clopidogrel regardless of aspirin dose , as follows : ≤100 mg , 10.5 % versus 8.6 % ( relative risk [ RR ] , 0.81 [ 95 % CI , 0.68 to 0.97 ] ) ; 101 to 199 mg , 9.8 % versus 9.5 % ( RR , 0.97 [ 95 % CI 0.77 to 1.22 ] ) ; and ≥200 mg , 13.6 % versus 9.8 % ( RR , 0.71 [ 95 % CI , 0.59 to 0.85 ] ) . The incidence of major bleeding increased with increasing aspirin dose both in the placebo group ( 1.9 % , 2.8 % , and 3.7 % , respectively ; P = 0.0001 ) and the clopidogrel group ( 3.0 % , 3.4 % , and 4.9 % , respectively ; P = 0.0009 ) ; thus , the excess risk with clopidogrel was 1.1 % , 1.2 % , and 1.2 % , respectively . The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 ( 95 % CI 1.29 to 2.72 ) in the placebo group , 1.6 ( 95 % CI 1.19 to 2.23 ) in the clopidogrel group , and 1.7 ( 95 % CI 1.36 to 2.20 ) in the combined group . Conclusions —In patients with ACS , adding clopidogrel to aspirin is beneficial regardless of aspirin dose . Bleeding risks increase with increasing aspirin dose , with or without clopidogrel , without any increase in efficacy . Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg , with or without clopidogrel From 1979 to 1985 2435 patients having had transient ischaemic attacks ( TIAs ) or minor ischaemic strokes , were enrolled in the UK TIA trial and were r and omised to receive either aspirin 300 mg , daily or aspirin 1200 mg or placebo . Analysis of reported upper gastrointestinal bleeding events ( defined as haematemesis or melaena , or both ) showed a risk of bleeding in a dose dependent manner , odds ratios ( 95 % CI ) for 300 mg of aspirin = 3.3 ( 1.2 to 9.0 ) and for 1200 mg = 6.4 ( 2.5 to 16.5 ) and , as would be expected , an increased risk of hospitalisation because of bleeding also in a dose dependent manner , odds ratio = 3.6 ( 0.7 to 17.2 ) for 300 mg and 8.7 ( 2.0 to 37.6 ) for 1200 mg . Further analysis suggested greater risks of bleeding from duodenal ulcers than gastric ulcers and that bleeding is more likely early in the course of treatment with aspirin used as secondary prevention . There was also an increased risk of lower gastrointestinal bleeding , defined as fresh blood per rectum for both doses of aspirin , odds ratio 1.8 ( 0.5 to 6.1 ) for 300 mg of aspirin , and 1.5 ( 0.4 to 5.3 ) for 1200 mg of aspirin From 1979 - 85 , 2435 patients with a transient ischaemic attack or minor ischaemic stroke were r and omly allocated to receive long term " blind " treatment with aspirin 600 mg twice daily ( n = 815 ) , aspirin 300 mg once daily ( n = 806 ) or placebo ( n = 814 ) . No patient was lost to follow up . The " intention to treat " comparison included all the serious vascular events and deaths which occurred before the end of the follow up period on 30 September 1986 . There was no difference in efficacy between the 300 mg and 1200 mg daily doses of aspirin , but the lower dose was undoubtedly less gastrotoxic . Also , there was no definite difference in the response of  males and females to aspirin . The odds of suffering a major stroke , myocardial infa rct ion or vascular death were 15 % less in the combined aspirin groups compared with the placebo group ( 95 % confidence interval 29 % reduction to 3 % increase in odds ) which is compatible with the continuing overview of all the similar trials of antiplatelet drugs where the relative reduction in odds was 25 % . There was no statistically significant reduction in the likelihood of either disabling major stroke and vascular death or vascular death occurring In order to evaluate the efficacy of low dose acetylsalicylic acid ( ASA ) for the secondary prevention of ischemic stroke , this cooperative multicenter clinical trial was conducted on a non-blind basis . Patients having a first transient ischemic attack ( TIA ) , reversible ischemic neurological deficit ( RIND ) or completed ischemic stroke were eligible for this trial . A total of 590 patients including 47 cases of TIA , 23 cases of RIND and 520 cases of completed stroke entered this study . These patients were allocated by the time of admission to one of the following 5 trial regimens : ( 1 ) vasodilators having no known inhibitory effect on platelet function ( control group ) , ( 2 ) dipyridamole ( DP ) 50 mg 3 times a day ( DP group ) , ( 3 ) ASA 300 mg once a day ( ASA 300 mg group ) , ( 4 ) ASA 300 mg once in combination with DP 50 mg 3 times a day ( ASADP group ) , and ( 5 ) ASA 100 mg once a day ( ASA1 group ) . No difference in effect between the control and DP groups was observed , nor between the ASA 300 mg and ASADP groups . Therefore , we combined the control and DP groups to make a non-ASA group , and joined the ASA 300 mg and ASADP groups to make an ASA3 group . The differences in the cumulative event-free rate appeared to be significant between the non-ASA group and the ASA3 group and also between the non-ASA group and the ASA1 group . But the frequency distribution of age , territory of stroke , diabetes mellitus , cardiac disease , hematological disease and hyperuricemia were significantly different among these 3 study groups . We thus included these covariates in the Cox 's proportional hazard model to control their possible confounding effects . ( ABSTRACT TRUNCATED AT 250 WORDS Background —This is the primary report of the large-scale evaluation of lotrafiban , an orally administered IIb/IIIa receptor antagonist , a unique trial with respect to the platelet antagonist , protocol design , and inclusion of cerebrovascular disease in a significant proportion of patients . Methods and Results — Patients with vascular disease were r and omized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator . Follow-up was for up to 2 years . The primary end point was the composite of all-cause mortality , myocardial infa rct ion , stroke , recurrent ischemia requiring hospitalization , and urgent revascularization . Of 9190 patients enrolled from 23 countries and 690 hospitals , 41 % had cerebrovascular disease at the time of entry , and 59 % had coronary artery disease .  Death occurred in 2.3 % of placebo-assigned patients and 3.0 % of lotrafiban-group patients ( hazard ratio 1.33 , 95 % CI 1.03 to 1.72 , P = 0.026 ) , and the cause of excess death was vascular related . There was no significant difference in the primary end point ( 17.5 % compared with 16.4 % , respectively ; hazard ratio 0.94 , 95 % CI 0.85 to 1.03 , P = 0.19 ) . Serious bleeding was more frequent in the lotrafiban group ( 8.0 % compared with 2.8 % ; P < 0.001 ) . Serious bleeding was more common among patients who received higher doses of aspirin ( > 162 mg/d ) , with or without lotrafiban . Conclusions —Lotrafiban , an orally administered platelet glycoprotein IIb/IIIa blocker , induced a 33 % increase in death rate , which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial . Although the dose of aspirin was not r and omly assigned , the finding of increased bleeding with doses > 162 mg/d is noteworthy Large clinical trials such as the second International Study of Infa rct Survival routinely gave patients with myocardial infa rct ion a chewed aspirin , yet there are no data to show whether chewing of aspirin is better , or worse , than swallowing a whole tablet . We performed a r and omized , placebo-controlled study to determine whether chewing aspirin or administering it in solution accelerates its absorption and antiplatelet activity . On separate days , 12 fasting volunteers ingested 325 mg of buffered aspirin , either by chewing a tablet for 30 seconds before swallowing it with 4 ounces of water , swallowing a whole tablet with 4 ounces of water , or drinking 4 ounces of Alka Seltzer . Frequent blood sample s were obtained for serum aspirin , salicylate , and thromboxane B2 ( TxB2 ) concentrations . With all formulations of aspirin , serum TxB2 decreased 50 % when the plasma aspirin concentration reached approximately 1,000 ng/ml . A 50 % and 90 % decrease in serum TxB2 occurred more quickly after chewing a tablet than after a tablet was swallowed whole . For example , the t 50 % for serum TxB2 inhibition was 5.0 + /- 0.6 minutes with the chewed tablet versus 12.0 + /- 2.3 minutes when the tablet was swallowed ( p = 0.01 ) . A 50 % decrease in serum TxB2 occurred 7.6 + /- 1.2 minutes after Alka Seltzer solution ( p = 0.04 vs chewing a tablet ; p = 0.13 vs swallowing a whole tablet ) . Chewing an aspirin tablet is the most effective way of accelerating absorption of aspirin  into the blood and shortening the time required for an antiplatelet effect BACKGROUND Aspirin is known to improve the outcome of patients who have had a cerebral transient ischemic attack , but the optimal dose of aspirin remains uncertain . Experimental evidence indicates that 30 mg of aspirin daily alters platelet aggregation more favorably than the 300-mg dose currently used in patients after transient ischemic attack or minor ischemic stroke . METHODS We assessed the effects of two doses of a water-soluble preparation of acetylsalicylic acid , or aspirin ( 30 mg vs. 283 mg a day ) , on the occurrence of death from all vascular causes , nonfatal stroke , or nonfatal myocardial infa rct ion in a double-blind , r and omized , controlled clinical trial in patients who had had a transient ischemic attack or minor stroke . A total of 3131 patients participated in the study . The mean follow-up was 2.6 years . RESULTS In the group assigned to receive 30 mg of aspirin , the frequency of death from vascular causes , nonfatal stroke , or nonfatal myocardial infa rct ion was 228 of 1555 ( 14.7 percent ) , as compared with 240 of 1576 ( 15.2 percent ) in the group assigned to receive 283 mg . The age- and sex-adjusted hazard ratio for the group receiving the lower dose was 0.91 ( 95 percent confidence interval , 0.76 to 1.09 ) . There were slightly fewer major bleeding complications in the 30-mg group than in the 283-mg group ( 40 vs. 53 ) , and significantly fewer reports of minor bleeding ( 49 vs. 84 ) . Fewer patients receiving 30 mg of aspirin reported gastrointestinal symptoms ( 164 vs. 179 ) and other adverse effects ( 73 vs. 90 ) . CONCLUSIONS Our data indicate that 30 mg of aspirin daily is no less effective in the prevention of vascular events than a 283-mg dose in patients with a transient ischemic attack or minor stroke , and has fewer adverse effects Data describing the pharmacokinetics and pharmacodynamics of low dose aspirin ( acetylsalicylic acid ; ASA ) are limited . This single-center study was design ed to determine the rate and extent of oral absorption of 80-mg ASA tablets in healthy , young male subjects and to assess the intra- and inter-subject variability of ASA pharmacokinetics and platelet aggregation effects . Ten subjects each received a single , open-label , oral 80-mg ASA dose on three separate days . Each dose was separated by a 2-week washout interval . Blood sample s for pharmacokinetic determinations of ASA and its metabolite , salicylic acid ( SA ) and platelet aggregation studies were obtained at scheduled timepoints before and up to 24 hours after each dose . Peak plasma ASA levels of 1 microgram/mL were achieved within 30 minutes . Peak plasma SA levels of approximately 4 micrograms/mL were attained in 1 hour . The terminal half-lives ( t1/2 ) of ASA and SA were 0.4 and 2.1 hours , respectively . Both ASA and SA pharmacokinetics and the platelet aggregation response to ASA exhibited considerable intra- and inter-subject variability . Inhibition of platelet aggregation was found to relate with ASA area under the plasma concentration versus time curve ( AUC ) BACKGROUND Aspirin products are known to cause irritation and injury to the gastric mucosa . The belief that enteric-coated and buffered varieties are less likely to occasion major upper-gastrointestinal bleeding ( UGIB ) than plain aspirin was tested in data from a multicentre case-control study . METHODS 550 incident cases of UGIB admitted to hospital with melaena or haematemesis and confirmed by endoscopy , and 1202 controls identified from population census lists , were interviewed about use of aspirin and other non-steroidal anti-inflammatory drugs ( NSAIDs ) during the 7 days before the onset of bleeding ( cases ) or interview ( controls ) . Relative risks of UGIB for each type of aspirin used regularly ( at least every other day ) were calculated overall , and according to dose , by multiple logistic regression , with control for age , sex , marital status , date , education , cigarette smoking , alcohol use , and use of NSAIDs . FINDINGS The relative risks of UGIB for plain , enteric-coated , and buffered aspirin at average daily doses of 325 mg or less were 2.6 , 2.7 , and 3.1 , respectively . At doses greater than 325 mg , the relative risk was 5.8 for plain and 7.0 for buffered aspirin ; there were insufficient data to evaluate enteric-coated aspirin at this dose level . There were no important differences in risk attributable to the three aspirin forms according to bleeding site ( gastric vs duodenal ) , or when users of NSAIDs were excluded . INTERPRETATION Use of low doses of enteric-coated or buffered aspirin carries a three-fold increase in the risk of major UGIB . The assumption that these formulations are less harmful than plain aspirin may be mistaken 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 BACKGROUND Inflammation may be important in the pathogenesis of atherothrombosis . We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk . METHODS We measured plasma C-reactive protein , a marker for systemic inflammation , in 543 apparently healthy men participating in the Physicians ' Health Study in whom myocardial infa rct ion , stroke , or venous thrombosis subsequently developed , and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years . Subjects were r and omly assigned to receive aspirin or placebo at the beginning of the trial . RESULTS Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infa rct ion ( 1.51 vs. 1.13 mg per liter , P<0.001 ) or ischemic stroke ( 1.38 vs. 1.13 mg per liter , P=0.02 ) , but not venous thrombosis ( 1.26 vs. 1.13 mg per liter , P=0.34 ) , than among men without vascular events . The men in the quartile with the highest levels of C-reactive protein values had three times the risk of myocardial infa rct ion ( relative risk , 2.9 ; P<0.001 ) and two times the risk of ischemic stroke ( relative risk , 1.9 ; P=0.02 ) of the men in the lowest quartile . Risks were stable over long periods , were not modified by smoking , and were independent of other lipid-related and non-lipid-related risk factors . The use of aspirin was associated with significant reductions in the risk of myocardial infa rct ion ( 55.7 percent reduction , P=0.02 ) among men in the highest quartile but with only small , nonsignificant reductions among those in the lowest quartile ( 13.9 percent , P=0.77 ) . CONCLUSIONS The base-line plasma concentration of C-reactive protein predicts the risk of future myocardial infa rct ion and stroke . Moreover , the reduction associated with the use of aspirin in the risk of a first myocardial infa rct ion appears to be directly related to the level of C-reactive protein , raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease OBJECTIVES This study was design ed to compare the efficacy of low and intermediate aspirin doses in acute coronary syndromes . BACKGROUND Little is known of the comparative efficacy of low and intermediate aspirin doses in this setting . METHODS We compared six-month death , myocardial infa rct ion ( MI ) , and stroke in patients with unstable angina or acute MI discharged while receiving low ( < 150 mg ) or intermediate ( > or = 150 mg ) aspirin therapy in the GUSTO IIb and PURSUIT trials ( n = 20,521 ) . We used multivariable analysis and performed a propensity analysis in order to adjust for baseline imbalances between the groups . RESULTS Aspirin doses < 150 mg were prescribed to 29.9 % ( 6,128 ) of patients . By six months , 6.4 % of the patients ( 1,310 of 20,521 ) had a primary event , 6.2 % of the patients receiving < 150 mg and 6.6 % of the patients receiving aspirin doses > or = 150 mg ( hazard ratio [ HR ] 1.06 [ 95 % confidence interval ( CI ) 0.94 to 1.19 ] , p = 0.35 ) . After adjusting for baseline imbalances and the propensity score for discharge aspirin dose , there was no effect of aspirin dose on the composite end point at six months ( HR 0.92 [ 95 % CI 0.79 to 1.07 ] , p = 0.28 ) . However , the higher aspirin dose was associated with a reduction in six-month MI ( HR 0.79 [ 95 % CI 0.64 to 0.98 ] , p = 0.03 ) . The outcome was similar when patients were matched on the basis of the propensity score for aspirin dose ( HR for death/MI/stroke 0.94 [ 95 % CI 0.80 to 1.12 ] , p = 0.51 ) , although stroke occurred significantly more frequently among patients receiving the higher aspirin dose ( HR 1.74 [ 95 % CI 1.01 to 3.02 ] p = 0.05 ) and the effect on MI was no longer apparent . CONCLUSIONS Although these data are non-r and omized , they suggest that the aspirin dose upon discharge may influence the clinical course after unstable angina or acute MI 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 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 In this study of healthy middle-aged and elderly subjects , we found that self-reported family history of premature heart attack and sudden death is independently associated with reduced HRV , suggesting that autonomic imbalance may be part of the complex of familial predisposition to premature heart attack BACKGROUND Endarterectomy benefits certain patients with carotid stenosis , but benefits are lessened by perioperative surgical risk . Acetylsalicylic acid lowers the risk of stroke in patients who have experienced transient ischaemic attack and stroke . We investigated appropriate doses and the role of acetylsalicylic acid in patients undergoing carotid endarterectomy . METHODS In a r and omised , double-blind , controlled trial , 2849 patients scheduled for endarterectomy were r and omly assigned 81 mg ( n=709 ) , 325 mg ( n=708 ) , 650 mg ( n=715 ) , or 1300 mg ( n=717 ) acetylsalicylic acid daily , started before surgery and continued for 3 months . We recorded occurrences of stroke , myocardial infa rct ion , and death . We compared patients on the two higher doses of acetylsalicylic acid with patients on the two lower doses . FINDINGS Surgery was cancelled in 45 patients , none were lost to follow-up by 30 days , and two were lost by 3 months . The combined rate of stroke , myocardial infa rct ion , and death was lower in the low-dose groups than in the high-dose groups at 30 days ( 5.4 vs 7.0 % , p=0.07 ) and at 3 months ( 6.2 vs 8.4 % , p=0.03 ) . In an efficacy analysis , which excluded patients taking 650 mg or more acetylsalicylic acid before r and omisation , and patients r and omised within 1 day of surgery , combined rates were 3.7 % and 8.2 % , respectively , at 30 days ( p=0.002 ) and 4.2 % and 10.0 % at 3 months ( p=0.0002 ) . INTERPRETATION The risk of stroke , myocardial infa rct ion , and death within 30 days and 3 months of endarterectomy is lower for patients taking 81 mg or 325 mg acetylsalicylic acid daily than for those taking 650 mg or 1300 mg All 701 heart infa rct ion patients admitted to 15 hospitals in the district of Cottbus between 1981 and 1983 were r and omly administered 30 , 60 or 1000 mg aspirin daily according to the territorial affiliation of their local hospitals . The physical and drug therapy during the 2 years follow-up was highly st and ardized ; deviations -- as far as they occurred -- were documented . Lower all-cause mortality was statistically demonstrated in patients over 60 and a lower fatal reinfa rct ion rate in patients over 50 as well as in men .  Deaths and fatal reinfa rct ions were significantly lower among patients with a history of angina pectoris , marked ST-depression , with an infa rct ion location except for the posterior wall and among hypercholesterolemic patients . The preventive effect of 60 mg aspirin daily was less than that of 30 mg in comparison to the 1000 mg group . Side effects were seen in 4 and 8 % ( first and second year ) , respectively , of the patients administered 30 mg aspirin as opposed to 22 and 17 % in patients allocated 1000 mg . We conclude that the optimum dose of aspirin for preventing reinfa rct ions could be as low as 30 mg daily 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 Of 1078 patients admitted to the coronary care unit with acute chest pain , 293 who had possible acute myocardial infa rct ion and symptoms of median 4 h duration were r and omized to treatment with acetylsalicylic acid ( ASA ) 100 mg daily , 1000 mg daily or placebo for 3 months . During hospitalization , the combined incidence of cardiac death and non-fatal myocardial infa rct ion on-treatment ( withdrawals not included ) was significantly lower ( P less than 0.02 ) in the 100 mg group ( 7.1 % ) than in both the 1000 mg group ( 20.8 % ) and the placebo group ( 19.7 % ) . During later time periods of treatment and at all time periods analysed according to the intention-to-treat principle ( withdrawals included ) , data suggested the same trend , but differences were not statistically significant . Collagen-induced platelet aggregation and serum thromboxane B2 were reduced to the same degree in the two ASA groups and were normal in the placebo group . The data suggest that low-dose ASA could be cheap and safe as first-aid therapy in myocardial infa rct ion suspects 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
target: 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
background: 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 .