***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: Background — Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism ( VTE ) in a previous trial . We undertook this study to extend those findings . Methods and Results — In a r and omized , double-blind , double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days , we compared dabigatran 150 mg twice daily with warfarin . The primary outcome , recurrent symptomatic , objective ly confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients ( 2.3 % ) compared with 28 of the 1289 warfarin patients ( 2.2 % ; hazard ratio , 1.08 ; 95 % confidence interval [ CI ] , 0.64–1.80 ; absolute risk difference , 0.2 % ; 95 % CI , −1.0 to 1.3 ; P<0.001 for the prespecified noninferiority margin for both criteria ) . The safety end point , major bleeding , occurred in 15 patients receiving dabigatran ( 1.2 % ) and in 22 receiving warfarin ( 1.7 % ; hazard ratio , 0.69 ; 95 % CI , 0.36–1.32 ) . Any bleeding occurred in 200 dabigatran ( 15.6 % ) and 285 warfarin ( 22.1 % ; hazard ratio , 0.67 ; 95 % CI , 0.56–0.81 ) patients . Deaths , adverse events , and acute coronary syndromes were similar in both groups . Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 ( 95 % CI , 0.76–1.57 ) , for major bleeding of 0.73 ( 95 % CI , 0.48–1.11 ) , and for any bleeding of 0.70 ( 95 % CI , 0.61–0.79 ) . Conclusion — Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE . Clinical Trial Registration — URL : www . clinical trials.gov . Unique identifiers : NCT00680186 and NCT00291330 Background — Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin , respectively . Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results . A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation . This study evaluated the potential of prothrombin complex concentrate ( PCC ) to reverse the anticoagulant effect of these drugs . Methods and Results — In a r and omized , double-blind , placebo-controlled study , 12 healthy male volunteers received rivaroxaban 20 mg twice daily ( n=6 ) or dabigatran 150 mg twice daily ( n=6 ) for 2½ days , followed by either a single bolus of 50 IU/kg PCC ( Cofact ) or a similar volume of saline . After a washout period , this procedure was repeated with the other anticoagulant treatment . Rivaroxaban induced a significant prolongation of the prothrombin time ( 15.8±1.3 versus 12.3±0.7 seconds at baseline ; P<0.001 ) that was immediately and completely reversed by PCC ( 12.8±1.0 ; P<0.001 ) . The endogenous thrombin potential was inhibited by rivaroxaban ( 51±22 % ; baseline , 92±22 % ; P=0.002 ) and normalized with PCC ( 114±26 % ; P<0.001 ) , whereas saline had no effect . Dabigatran  increased the activated partial thromboplastin time , ecarin clotting time ( ECT ) , and thrombin time . Administration of PCC did not restore these coagulation tests . Conclusion — Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study . Clinical Trial Registration — URL : http://www.trialregister.nl . Unique identifier : NTR2272 BACKGROUND Apixaban , an oral potent reversible direct inhibitor of activated factor X , has shown promise in the prevention of venous thromboembolism following major orthopedic surgery . We conducted a dose-ranging study in patients with deep vein thrombosis . METHODS Consecutive patients with symptomatic deep vein thrombosis were included and r and omized to receive 84 - 91 days of apixaban 5 mg twice-daily , 10 mg twice-daily , or 20 mg once-daily , or low molecular weight heparin ( LMWH ) followed by a vitamin K antagonist ( VKA ) . The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan . The principal safety outcome was the composite of major and clinical ly relevant , non-major bleeding . RESULTS The mean age of the 520 included patients was 59 years , and 62 % were male . The primary outcome occurred in 17 of the 358 apixaban-treated patients [ 4.7 % , 95 % confidence interval ( CI ) 2.8 - 7.5 % ] and in five of the 118 LMWH/VKA-treated patients ( 4.2 % , 95 % CI 1.4 - 9.6 % ) who were evaluable . The incidence in all three apixaban groups was low and comparable without evidence of a dose response . The principal safety outcome occurred in 28 ( 7.3 % ) of the 385 apixaban-treated patients and in 10 ( 7.9 % ) of the 126 LMWH/VKA-treated patients . No dose response for apixaban was observed . CONCLUSION These observations warrant further evaluation of apixaban in phase III studies . The attractive fixed-dose regimen of this compound may meet the dem and to simplify anticoagulant treatment in patients with established venous thromboembolism BACKGROUND Apixaban , an oral factor Xa inhibitor administered in fixed doses , may simplify the treatment of venous thromboembolism . METHODS In this r and omized , double-blind study , we compared apixaban ( at a dose of 10 mg twice daily for 7 days , followed by 5 mg twice daily for 6 months ) with conventional therapy ( subcutaneous enoxaparin , followed by warfarin ) in 5395 patients with acute venous thromboembolism . The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism . The principal safety outcomes were major bleeding alone and major bleeding plus clinical ly relevant nonmajor bleeding . RESULTS The primary efficacy outcome occurred in 59 of 2609 patients ( 2.3 % ) in the apixaban group , as compared with 71 of 2635 ( 2.7 % ) in the conventional-therapy group ( relative risk , 0.84 ; 95 % confidence interval [ CI ] , 0.60 to 1.18 ; difference in risk [ apixaban minus conventional therapy ] , -0.4 percentage points ; 95 % CI , -1.3 to 0.4 ) . Apixaban was noninferior to conventional therapy ( P<0.001 ) for predefined upper limits of the 95 % confidence intervals for both relative risk ( < 1.80 ) and difference in risk ( < 3.5 percentage points ) . Major bleeding occurred in 0.6 % of patients who received apixaban and in 1.8 % of those who received conventional therapy ( relative risk , 0.31 ; 95 % CI , 0.17 to 0.55 ; P<0.001 for superiority ) . The composite outcome of major bleeding and clinical ly relevant nonmajor bleeding occurred in 4.3 % of the patients in the apixaban group , as compared with 9.7 % of those in the conventional-therapy group ( relative risk , 0.44 ; 95 % CI , 0.36 to 0.55 ; P<0.001 ) . Rates of other adverse events were similar in the two groups . CONCLUSIONS A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding ( Funded by Pfizer and Bristol-Myers Squibb ; Clinical Trials.gov number , NCT00643201 ) Background and Purpose — Intracranial hemorrhage is the most devastating complication of anticoagulation . Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined . Methods — Analysis of 18 113 participants with atrial fibrillation in the R and omized Evaluation of Long-term anticoagulant therapY ( RE-LY ) trial assigned to adjusted-dose warfarin ( target international normalized ratio , 2–3 ) or dabigatran ( 150 mg or 110 mg , both twice daily ) . Results — During a mean of 2.0 years of follow-up ,  154 intracranial hemorrhages occurred in 153 participants : 46 % intracerebral ( 49 % mortality ) , 45 % subdural ( 24 % mortality ) , and 8 % subarachnoid ( 31 % mortality ) . The rates of intracranial hemorrhage were 0.76 % , 0.31 % , and 0.23 % per year among those assigned to warfarin , dabigatran 150 mg , and dabigatran 110 mg , respectively ( P<0.001 for either dabigatran dose versus warfarin ) . Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg ( n=13 and n=11 , respectively ) versus warfarin ( n=32 ; P<0.01 for both ) . Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran ( 11 patients with each dose ) compared with warfarin ( 24 patients ; P<0.05 for both dabigatran doses versus warfarin ) . Independent predictors of intracranial hemorrhage were assignment to warfarin ( relative risk , 2.9 ; P<0.001 ) , aspirin use ( relative risk , 1.6 ; P=0.01 ) , age ( relative risk , 1.1 per year ; P<0.001 ) , and previous stroke/transient ischemic attack ( relative risk , 1.8 ; P=0.001 ) . Conclusions — The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran . Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin . Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation ( AF ) . In this 12-week , parallel-group , multicentre , multinational study , 1,146 patients with AF and risk of stroke were r and omised to edoxaban 30 mg qd , 30 mg bid , 60 mg qd , or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0 - 3.0 . The study was double-blind to edoxaban dose , but open-label to warfarin . Primary outcomes were occurrence of major and /or clinical ly relevant non-major bleeding and elevated hepatic enzymes and /or bilirubin .  Mean age was 65 + /- 8.7 years and 64.4 % were warfarin-naïve . Whereas major plus clinical ly relevant non-major bleeding occurred in 3.2 % of patients r and omised to warfarin , the incidence of bleeding was significantly higher with the edoxaban 60 mg bid ( 10.6 % ; p=0.002 ) and 30 mg bid regimens ( 7.8 % ; p=0.029 ) , but not with the edoxaban 60 mg qd ( 3.8 % ) or 30 mg qd regimens ( 3.0 % ) . For the same total daily dose of 60 mg , both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group . There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups . The safety profiles  of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin . In contrast , the edoxaban bid regimens were associated with more bleeding than warfarin . These results 
    Output:
    
The reduced odds of fatal bleeding with NOACs was not demonstrated after controlling for bleeding location .
AUTHOR ’S CONCLUSIONS : The odds ratio calculated in this meta- analysis showed a reduced odds of death in major bleeding associated with NOAC use .
This risk reduction was due to a disproportionate amount of intracranial bleeding in the VKA arms .
For any given bleeding site , there was no evidence of a significant difference in fatal outcomes from bleeds associated with NOAC versus VKA use .