***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 
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    Input: BACKGROUND Treatment with warfarin sodium is effective for stroke prevention in atrial fibrillation but many physicians hesitate to prescribe it to elderly patients presumably because of the associated risk for bleeding and the inconvenience of frequent blood tests for the patients . METHODS In the Second Copenhagen Atrial Fibrillation , Aspirin , and Anticoagulation ( AFASAK 2 ) Study , we studied the rate of bleeding events associated with the incidence of thromboembolic events in patients receiving warfarin sodium , 1.25 mg/d ; warfarin sodium , 1.25 mg/d , plus aspirin , 300 mg/d ; aspirin , 300 mg/d ; or adjusted-dose warfarin therapy aim ing at an international normalized ratio of the prothrombin time ratio ( INR ) of 2.0 to 3.0 . The study was scheduled for 6 years from May 1 , 1993 , but owing to evidence of inefficiency of low-intensity therapy plus aspirin from another study it was prematurely terminated on October 2 , 1996 . Minor and major bleeding events were recorded prospect ively . The rate of bleeding was calculated using the Kaplan-Meier method and risk factors were identified by the Cox proportional hazards model . RESULTS Of 677 included patients , 130 ( median age , 77 years ; range , 67 - 89 years ) experienced bleeding . One woman and 12 men experienced major bleeding . Four had intracranial bleeding : 2 cases were fatal and 2 were nonfatal . During treatment with mini-dose warfarin , warfarin plus aspirin , aspirin , and adjusted-dose warfarin , the annual rate of major bleeding was 0.8 % , 0.3 % , 1.4 % , and 1.1 % , respectively ( P = .20 ) . After 3 years of treatment the cumulative rate of any bleeding was 24.7 % , 24.4 % , 30.0 % , and 41.1 % ( P = .003 ) , respectively . Increasing INRvalue ( P<.001 ) and prior myocardial infa rct ion ( P = .001 ) were independent risk factors for bleeding , whereas increasing age was not . CONCLUSIONS Fixed mini-dose warfarin and aspirin alone or in combination were associated with both minor and major bleeding . The small number of major bleeding events in patients receiving adjusted-dose warfarin therapy as compared with those receiving less intensive antithrombotic treatments and the finding of no significant influence of age on the risk for bleeding indicate that even elderly patients with atrial fibrillation tolerate adjusted-dose warfarin therapy ( INR , 2.0 - 3.0 ) BACKGROUND AND PURPOSE Recent clinical trials have established that adjusted-dose warfarin ( international normalized ratio [ INR ] 2.0 to 3.0 ) is highly effective in the reduction of ischemic stroke in patients with nonvalvular atrial fibrillation ( AF ) . We hypothesized that the introduction of fixed low-dose warfarin alone or in combination with aspirin ( 300 mg ) could normalize hemostatic markers , namely plasma fibrin D-dimer ( an index of thrombogenesis ) , plasminogen activator inhibitor-1 ( PAI-1 , an index of fibrinolysis ) , fibrinogen , and von Willebr and factor ( vWf , an index of endothelial dysfunction ) , in a manner comparable to adjusted-dose warfarin ( target INR 2.0 to 3.0 ) . METJODS : Sixty-one patients with AF ( 44 men , mean+/-SD age 64+/-19 years ) who were not receiving any antithrombotic therapy were prospect ively r and omized into 1 of 3 treatment groups : warfarin ( 2 mg ) ( n=23 ; group 1 ) , combination 1 mg warfarin plus 300 mg aspirin ( n=21 ; group 2 ) or combination 2 mg warfarin plus 300 mg aspirin ( n=17 ; group 3 ) . Subjects from all 3 AF groups were matched for sex , age , and blood pressure . Blood sample s were taken for sequential measurements for changes in plasma fibrin D-dimer , PAI-1 , fibrinogen , and vWf before and at 2 and 8 weeks after r and omization ( phase 1 ) . All patients were subsequently offered adjusted-dose warfarin therapy ( phase 2 ) , and an additional blood sample was taken 6 weeks later . RESULTS When pretreatment results were compared with those from 60 age- and sex-matched healthy control subjects in sinus rhythm , there were significant elevations in levels of fibrinogen ( P=0.025 ) , vWf ( P<0.0001 ) , and fibrin D-dimer ( P<0.0001 ) in patients with AF compared with control subjects . There were no significant changes in the levels of various indices measured after 2 and 8 weeks of therapy in all 3 groups , except for an increase in PAI-1 level ( P=0.024 ) in group 3 . After 6 weeks of therapy with dose-adjusted warfarin ( INR 2.0 to 3.0 ) , there was a significant decrease in plasma fibrinogen ( P=0.023 ) and fibrin D-dimer ( P=0.0067 ) levels . There were no significant changes in the levels of PAI-1 ( P=0.198 ) or vWf ( P=0.33 ) . CONCLUSIONS The present results confirmed that high levels of vWf , fibrinogen , and fibrin D-dimer levels were present in patients with AF compared with control subjects . Moreover , the introduction of 300 mg aspirin plus low-dose warfarin ( 1 mg/d ) , low-dose warfarin alone ( 2 mg/d ) , or 300 mg aspirin plus low-dose warfarin ( 2 mg/d ) did not significantly reduce any of the hemostatic markers studied ( except PAI-1 levels ) , whereas conventional full-dose warfarin ( INR 2.0 to 3.0 ) significantly reduced levels of fibrin D-dimer and fibrinogen . These results are in keeping with the disappointing ineffectiveness of low-intensity warfarin therapy , aspirin-warfarin combination , and ultralow-dose warfarin therapy in the recent prematurely terminated clinical trials and the established benefits of conventional adjusted-dose anticoagulation therapy OBJECTIVES This trial evaluated the efficacy and safety of the combination of antiplatelet and moderate-intensity anticoagulation therapy in patients with atrial fibrillation associated with recognized risk factors or mitral stenosis . BACKGROUND Warfarin was more effective than aspirin in preventing stroke in these patients ; combined therapy with low anticoagulant intensity was ineffective . Mitral stenosis patients were not investigated . METHODS We performed a multicenter r and omized trial in 1,209 patients at risk . The intermediate-risk group included patients with risk factors or age > 60 years : 242 received the cyclooxygenase inhibitor triflusal  , 237 received  acenocumarol , and 235 received a combination of both .  The high-risk group included patients with prior embolism or mitral stenosis : 259 received anticoagulants and 236 received the combined therapy . Median follow-up was 2.76 years . Primary outcome was a composite of vascular death and nonfatal stroke or systemic embolism . RESULTS Primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate- ( hazard ratio [ HR ] 0.33 [ 95 % confidence interval (CI)0.12 to 0.91 ] ; p = 0.02 ) and the high-risk group ( HR 0.51 [ 95 % CI 0.27 to 0.96 ] ; p = 0.03 ) . Primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group . Nonvalvular and mitral stenosis patients had similar embolic event rates during anticoagulant therapy . CONCLUSIONS The combined antiplatelet plus moderate-intensity anticoagulation therapy significantly decreased the vascular events compared with anticoagulation alone and proved to be safe in atrial fibrillation patients Authors studied the effect of coumarin , and its combination with low-dose ( 125 mg/day ) acetylsalicylic acid in the prevention of thromboembolic complication during a 10-year period ( average 4.7 years ) in a r and omized trial of 296 patients aged 18 - 60 year with tilting disc type prosthetic heart valve ( 159 mitral and 137 aortic ) in sinus rhythm . In the group treated with coumarin ( 152 patients , 743.4 patient-years ) 4 cases ( 2 of them fatal ) of valve thrombosis , 12 cases of peripheral embolism and 9 cases ( 3 intracranial , 3 among them fatal ) of major bleeding were observed ; in the group treated with coumarin plus acetylsalicylic acid ( 144 patients , 638.7 patient-years ) 2 cases ( 1 of them fatal ) of valve thrombosis , 4 cases of peripheral embolism and 14 cases ( 3 of them fatal ) of major bleeding were observed . In the case of valve thromboses the difference between the two groups was non-significant but still clinical ly remarkable ; peripheral embolism occurred in significantly higher number ( p < 0.05 ) . There was no statistically significant difference of bleeding complications between the two groups . The results suggest that the combination of coumarin plus low-dose acetylsalicylic acid is more effective in the prevention of thromboembolic complications in patients with mitral and aortic prosthetic heart valve than coumarin alone ; the danger of bleeding complications seems to be acceptable with adequate control To explore whether antithrombotic medication may protect against cognitive decline , tests of verbal memory , attention , abstract reasoning , verbal fluency , and mental flexibility were administered to 405 men at risk of cardiovascular disease . These subjects were a subgroup of those who had been participating in a r and omised double blind factorial trial of low dose aspirin ( 75 mg daily ) and low intensity oral anticoagulation with warfarin ( international normalised ratio of 1.5 ) at 35 general practice s across the United Kingdom for at least five years , were at least 55 years old at trial entry , and had been r and omly allocated to one of four groups : active warfarin and active aspirin , active warfarin and placebo aspirin , placebo warfarin and active aspirin , and double placebo .  Verbal fluency and mental flexibility were significantly better in subjects taking antithrombotic medication than in subjects taking placebo . Aspirin may have contributed more than warfarin to any beneficial effect . These results provide tentative evidence that antithrombotic medication may protect cognitive function in men at risk of cardiovascular disease The scientific community 's quest for unbiased research received a strong boost from a recent policy amendment on r and omised controlled trials ( RCTs ) in this journal . Henceforth , the status of allocation concealment will be clearly indicated in the abstract s along with that of blinding . Thus , readers will have additional information by which to judge the internal validity of trials . In this editorial I address the background and rationale for these enhancements . R and om allocation to intervention groups remains the only method of ensuring that the groups being compared are on an equivalent footing at the outset of the study , thus eliminating selection and confounding biases . This has allowed RCTs to play a key part in advancing medical science . The success of r and omisation depends on 2 interrelated processes.1 , 2 The first entails generating a sequence by which the participants in a trial are allocated to intervention groups . To ensure unpredictability of that allocation sequence , investigators should generate it by a r and om process . The second process , allocation concealment , shields those involved in a trial from knowing upcoming assignments in advance.3 , 4 Without this protection , investigators and patients have been known to change who gets the next assignment , making the comparison groups less equivalent.5 , 6 For example , suppose that an investigator creates an adequate allocation sequence using a r and om number table . However , the investigator then affixes the list of that sequence to a bulletin board , with no allocation concealment . Those responsible for admitting participants could ascertain the upcoming treatment allocations and then route participants with better prognoses to the experimental group and those with poorer prognoses to the control group , or vice versa . Bias would result . Inadequate allocation concealment also Background — Patients with a non – ST-elevation acute coronary syndrome and prior CABG are at high risk of a recurrent ischemic event despite aspirin therapy . This trial investigated the potential benefit of secondary prevention with warfarin . Methods and Results —In a double-blind r and omized trial , 135 patients with unstable angina or non – ST-segment elevation myocardial infa rct ion , with prior CABG , and who were poor c and i date s for a revascularization procedure received therapy with aspirin and placebo+warfarin , warfarin and placebo+aspirin , or aspirin and warfarin for 12 months . Warfarin was titrated to an international normalized ratio of 2.0 to 2.5 . The primary end point ( death or myocardial infa rct ion or unstable angina requiring hospitalization 1 year after r and omization ) occurred in 14.6 % of the patients in the warfarin-alone group , in 11.5 % of patients in the aspir 
    Output:
    
Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve , given the question able benefits in reducing thromboembolic events and the increased risk of major bleeding