***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 Therapeutic decisions in atrial fibrillation ( AF ) are often influenced by assessment of bleeding risk . However , existing bleeding risk scores have limitations . Objectives We sought to develop and vali date a novel bleeding risk score using routinely available clinical information to predict major bleeding in a large , community-based AF population . Methods We analysed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation ( ORBIT-AF ) , a prospect i ve registry that enrolled incident and prevalent AF patients at 176 US sites . Using Cox proportional hazards regression , we identified factors independently associated with major bleeding among patients taking oral anticoagulation ( OAC ) over a median follow-up of 2 years ( interquartile range = 1.6–2.5 ) . We also created a numerical bedside risk score that included the five most predictive risk factors weighted according to their strength of association with major bleeding . The predictive performance of the full model , the simple five-item score , and two existing risk scores ( hypertension , abnormal renal/liver function , stroke , bleeding history or predisposition , labile INR , elderly , drugs/alcohol concomitantly , HAS-BLED , and anticoagulation and risk factors in atrial fibrillation , ATRIA ) were then assessed in both the ORBIT-AF cohort and a separate clinical trial population , Rivaroxaban Once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation ( ROCKET-AF ) . Results Among 7411 ORBIT-AF patients taking OAC , the rate of major bleeding was 4.0/100 person-years . The full continuous model ( 12 variables ) and five-factor ORBIT risk score ( older age [ 75 + years ] , reduced haemoglobin/haematocrit/history of anaemia , bleeding history , insufficient kidney function , and treatment with antiplatelet ) both had good ability to identify those who bled vs. not ( C-index 0.69 and 0.67 , respectively ) . These scores both had similar discrimination , but markedly better calibration when compared with the HAS-BLED and ATRIA scores in an external validation population from the ROCKET-AF trial . Conclusions The five-element ORBIT bleeding risk score had better ability to predict major bleeding in AF patients when compared with HAS-BLED and ATRIA risk scores . The ORBIT risk score can provide a simple , easily remembered tool to support clinical decision making Better underst and ing of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism ( VTE ) may help physicians when deciding on intensity and duration of treatment . The primary aim of this study was to identify risk factors for major and clinical ly relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE . We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study . Bleeding risk factors were evaluated in 4118 patients who received edoxaban  and significant variables were combined in a prediction model . We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation . Major bleeding occurred in 56/4118 ( 1.4 % ) patients given edoxaban and in 66/4122 ( 1.6 % ) patients given warfarin . Clinical ly relevant bleeding occurred in 349 ( 8.5 % ) and 423 ( 10.3 % ) , respectively . Significant risk factors for major bleeding during edoxaban treatment were female sex , concomitant antiplatelet therapy , haemoglobin ≤10 g/dl , history of arterial hypertension , and systolic blood pressure > 160 mmHg . The discrimination of the model was high ( C-statistic : 0.71 ) for major bleeding , lower for clinical ly relevant bleeding ( C-statistic : 0.62 ) and when the model was applied to patients receiving warfarin ( C-statistic 0.60 ) . In conclusion , we identified five main predictors of major bleeding in  patients receiving edoxaban for the treatment of acute VTE . A risk model based on these factors predicted an increased risk of bleeding with good discrimination Attempts at identifying patients with an elevated risk of bleeding while on anticoagulation following acute venous thromboembolism ( VTE ) have largely been unsuccessful thus far . We sought to develop a clinical prediction score for bleeding during stable anticoagulation treatment  after acute VTE . We performed a post hoc analysis of the pooled RE-COVER studies , two double-blind r and omised “ sister ” trials evaluating dabigatran versus st and ard treatment in 5107 VTE patients . A score was derived from patients r and omised to dabigatran using logistic regression analysis covering the complete follow-up period . The final model , named VTE-BLEED , included six variables and yielded a c-statistic of 0.72 ( 95 % CI 0.67–0.76 ) . Patients from the derivation cohort in the low-risk group ( < 2 points ; 74 % of the derivation population ) had a bleeding incidence of 2.8 % compared to 12.6 % in the elevated-risk group ( OR 5.0 ; 95 % CI 3.5–7.1 ) . The score proved accurate for our primary end-point , i.e. prediction of major bleeding after day 30 ( “ stable ” anticoagulation ) , both in patients on dabigatran ( c-statistic 0.75 , 95 % CI 0.61–0.89 ) and those on warfarin ( 0.78 , 95 % CI 0.68–0.86 ; p=0.77 for difference ) . The new VTE-BLEED score accurately predicted major bleeding events in VTE patients on stable anticoagulation with both dabigatran and warfarin . The new VTE-BLEED score predicted major bleeding events in VTE patients on stable anticoagulation treatment Existing clinical scores do not perform well in predicting bleeding in elderly patients with acute venous thromboembolism ( VTE ) . We sought to derive an easy-to-use clinical score to help physicians identify elderly patients with VTE who are at high-risk of bleeding during extended anticoagulation ( > 3 months ) . Our derivation sample included 743 patients aged ≥65 years with VTE who were enrolled in a prospect i ve multicenter cohort study . All patients received extended anticoagulation with vitamin K antagonists . We derived our score using competing risk regression , with the time to a first major bleeding up to 36 months of extended anticoagulation as the outcome , and 17 c and i date variables as predictors . We used bootstrapping methods for internal validation . Sixty-six ( 9 % ) patients suffered major bleeding . The clinical score is based on seven clinical factors ( previous bleeding , active cancer , low physical activity , anemia , thrombocytopenia , antiplatelet drugs/NSAIDs , and poor INR control ) . Overall , 48 % of patients were classified as low-risk , 37 % as moderate-risk , and 15 % as high-risk of bleeding . The rate of major bleeding was 1.4 events in low-risk , 5.0 events in moderate-risk , and 12.2 events per 100 patient-years in high-risk patients . The c-statistic was 0.78 at 3 months and 0.71 at 36 months of extended anticoagulation . Model calibration was excellent ( p=0.93 ) . Internal validation showed similar results . This simple clinical score accurately identified elderly patients with VTE who are at high risk of major bleeding and who may not benefit from extended anticoagulation . Further validation of the score is important before its implementation into practice . The study is registered to https:// clinical trials.gov as NCT00973596 PURPOSE To determine the incidence of major bleeding in out patients treated with warfarin  and to identify predictive factors known at the start of therapy . PATIENTS AND METHODS The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were review ed . Follow-up information was obtained for 562 patients ( 99.5 % ) .  Bleeding was classified as major or minor using explicit criteria . The cumulative incidence of bleeding was estimated by means of survival analysis . Independent risk factors for major bleeding were identified using Cox regression analysis in 375 r and omly chosen patients ; they were tested in the remaining 187 patients . RESULTS Major bleeding occurred in 65 patients ( 12 % ) and was fatal in 10 patients ( 2 % ) . The cumulative incidences of major bleeding at one , 12 , and 48 months were 3 % , 11 % , and 22 % , respectively . The monthly risk of major bleeding decreased over time , from 3 % during the first month of outpatient therapy to 0.3 % per month after the first year of therapy . Five independent risk factors for major bleeding -- age 65 years or greater , history of stroke , history of gastrointestinal bleeding , a serious comorbid condition ( recent myocardial infa rct ion , renal insufficiency , or severe anemia ) , atrial fibrillation -- predicted major bleeding in the testing group ; the cumulative incidence of major bleeding at 48 months was 2 % in 57 low-risk patients , 17 % in 110 middle-risk patients , and 63 % in 20 high-risk patients . CONCLUSION These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin . Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined PURPOSE To evaluate the accuracy and clinical utility of the Outpatient Bleeding Risk Index for estimating the probability of  major bleeding in out patients treated with warfarin .  The index was previously derived in a retrospective cohort of 556 patients from a different hospital ( derivation cohort ) . SUBJECTS AND METHODS We enrolled 264 out patients starting warfarin ( validation cohort ) to vali date the index prospect ively . All patients were identified upon hospital discharge , and physician estimates of the probability of major bleeding were obtained before discharge in the validation cohort . RESULTS Major bleeding occurred in 87 of 820 out patients ( 6.5%/yr ) . The index included four independent risk factors for major bleeding : age 65 years or greater ; history of gastrointestinal bleeding ; history of stroke ; and one or more of four specific comorbid conditions . In the validation cohort , the index predicted major bleeding : the cumulative incidence at 48 months was 3 % in 80 low-risk patients , 12 % in 166 intermediate-risk patients , and 53 % in 18 high-risk patients ( c index , 0.78 ) . The index performed better than physicians , who estimated the probability of major bleeding no better than expected by chance . Of the 18 episodes of major bleeding that occurred in high-risk patients , 17 were potentially preventable . CONCLUSIONS The Outpatient Bleeding Risk Index prospect ively classified patients according to risk of major bleeding and performed better than physicians . Major bleeding may be preventable in many high-risk patients by avoidance of over-anticoagulation and nonsteroidal anti-inflammatory agents BACKGROUND St and ard therapy to prevent recurrent venous thromboembolism includes 3 to 12 months of treatment with full-dose warfarin with a target international normalized ratio ( INR ) between 2.0 and 3.0 . However , for long-term management , no therapeutic agent has shown an acceptable benefit-to-risk ratio . METHODS Patients with idiopathic venous thromboembolism who had received full-dose anticoagulation therapy for a median of 6.5 months were r and omly assigned to  placebo or low-intensity warfarin ( target INR , 1.5 to 2.0 ) . Participants were followed for recurrent venous thromboembolism , major hemorrhage , and death . RESULTS The trial was terminated early after 508 patients had undergone r and omization and had been followed for up to 4.3 years ( mean , 2.1 ) . Of 253 patients assigned to placebo  , 37 had recurrent venous thromboembolism ( 7.2 per 100 person-years ) , as compared with 14 of 255 patients assigned to low-intensity warfarin ( 2.6 per 100 person-years ) , a risk reduction of 64 percent ( hazard ratio , 0.36 [ 95 percent confidence interval , 0.19 to 0.67 ] ; P<0.001 ) . Risk reductions were similar for all subgroups , including those with and those without inherited thrombophilia . Major hemorrhage occurred in two patients assigned to placebo and five assigned to low-intensity warfarin ( P=0.25 ) . Eight patients in the placebo group and four in the group assigned to low-intensity warfarin  died ( P=0.26 ) . Low-intensity warfarin was thus associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism , major hemorrhage , or death . According to per- protocol and as-treated analyses , the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent . CONCLUSIONS Long-term , low-intensity warfarin therapy is a highly effective method of preventing recurrent venous thromboembolism A score that can accurately determine the risk of major bleeding during anticoagulant therapy may help to make decisions on anticoagulant use . 
    Output:
    
Discussion The planned systematic review and meta- analysis will provide reliable estimates of the risk for major bleeding events during extended anticoagulation .