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 .
Dose Effects of Aspirin on Gastric Prostaglandins and Stomach Mucosal Injury
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
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 .