human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 r 
    Output:
    
agent
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
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 r 
    Output:
    