***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 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 There is a clinical need for new oral anticoagulants to prevent and treat thromboembolic diseases . Given its integral role in the coagulation cascade , factor Xa is a particularly promising target for new anticoagulation therapies . The aim of this study was to investigate the safety , pharmacodynamics , and pharmacokinetics of BAY 59–7939 , an oral , direct factor Xa inhibitor 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 suggest that in this three-month study , edoxaban 30 or 60 mg qd are safe and well-tolerated Edoxaban is an oral , reversible , direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation ( AF ) . A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS2 score ≥1 . In a multicentre , active-controlled , double-blind edoxaban and open-label warfarin , parallel-group study , a total of 235 patients from four Asian countries were r and omly assigned to edoxaban 30 mg qd , 60 mg qd or warfarin dose adjusted to international normalised ratio of 2 - 3 for three months . The primary endpoint was the incidence of central ly adjudicated all bleeding events ( major , clinical ly relevant non-major and minor ) . Secondary endpoints included thromboembolic events , biomarkers of thrombus formation and all adverse events ( AEs ) . The incidence of all bleeding events ( 95 % CI ) was 20.3 % ( 12.9 , 30.4 ) for edoxaban 30 mg , 23.8 % ( 15.8 , 34.1 ) for edoxaban 60 mg , and 29.3 % ( 20.2 , 40.4 ) for warfarin . A subgroup analysis suggested low body weight ( ≤60 kg ) may affect the incidence of bleeding  events with edoxaban . The incidence of study drug-related AEs was 22 % for edoxaban 30 mg , 29 % for edoxaban 60 mg and 33 % for warfarin . No thromboembolic events occurred in any treatment group . In conclusion , this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients  with edoxaban 30 mg and 60 mg compared with warfarin . Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group BACKGROUND Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use . Dabigatran is a new oral direct thrombin inhibitor . METHODS In this noninferiority trial , we r and omly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive , in a blinded fashion , fixed doses of dabigatran--110 mg or 150 mg twice daily -- or , in an unblinded fashion , adjusted-dose warfarin . The median duration of the follow-up period was 2.0 years . The primary outcome was stroke or systemic embolism . RESULTS Rates of the primary outcome were 1.69 % per year in the warfarin group , as compared with 1.53 % per year in the group that received 110 mg of dabigatran ( relative risk with dabigatran , 0.91 ; 95 % confidence interval [ CI ] , 0.74 to 1.11 ; P<0.001 for noninferiority ) and 1.11 % per year in the group that received 150 mg of dabigatran ( relative risk , 0.66 ; 95 % CI , 0.53 to 0.82 ; P<0.001 for superiority ) . The rate of major bleeding was 3.36 % per year in the warfarin group , as compared with 2.71 % per year in the group receiving 110 mg of dabigatran ( P=0.003 ) and 3.11 % per year in the group receiving 150 mg of dabigatran ( P=0.31 ) . The rate of hemorrhagic stroke was 0.38 % per year in the warfarin group , as compared with 0.12 % per year with 110 mg of dabigatran ( P<0.001 ) and 0.10 % per year with 150 mg of dabigatran ( P<0.001 ) . The mortality rate was 4.13 % per year in the warfarin group , as compared with 3.75 % per year with 110 mg of dabigatran ( P=0.13 ) and 3.64 % per year with 150 mg of dabigatran ( P=0.051 ) . CONCLUSIONS In patients with atrial fibrillation , dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin , as well as lower rates of major hemorrhage .  Dabigatran administered at a dose of 150 mg , as compared with warfarin , was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage . ( Clinical Trials.gov number , NCT00262600 . BACKGROUND Heparins and warfarin are currently used as venous thromboembolism ( VTE ) prophylaxis in surgery . Inhibition of factor ( F ) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit-risk profile . OBJECTIVES To evaluate the safety and efficacy of apixaban , a potent , direct , oral inhibitor of FXa , in patients following total knee replacement ( TKR ) , and to investigate dose-response relationships . PATIENTS / METHODS A total of 1238 patients were r and omized to one of six double-blind apixaban doses [ 5 , 10 or 20 mg day(-1 ) administered as a single ( q.d . ) or a twice-daily divided dose ( b.i.d . ) ] , enoxaparin ( 30 mg b.i.d . ) or open-label warfarin ( titrated to an International Normalized Ratio of 1.8 - 3.0 ) . Treatment lasted 10 - 14 days , commencing 12 - 24 h after surgery with apixaban or enoxaparin , and on the evening of surgery with warfarin . The primary efficacy outcome was a composite of VTE ( m and atory venography ) and all-cause mortality during treatment . The primary safety outcome was major bleeding . RESULTS A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis . All apixaban groups had lower primary efficacy event rates than either comparator . The primary outcome rate decreased with increasing apixaban dose ( P = 0.09 with q.d./b.i.d . regimens combined , P = 0.19 for q.d . and P = 0.13 for b.i.d . dosing).A significant dose-related increase in the incidence of total adjudicated bleeding events was noted in the q.d . ( P = 0.01 ) and b.i.d . ( P = 0.02 ) apixaban groups ; there was no difference between q.d . and b.i.d . regimens . CONCLUSIONS Apixaban in doses of 2.5 mg b.i.d . or 5 mg q.d . has a promising benefit-risk profile compared with the current st and ards of care following TKR OBJECTIVE The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of rivaroxaban -- a novel , oral , direct Factor Xa ( FXa ) inhibitor -- in healthy elderly subjects . RESEARCH DESIGN AND METHODS In this single-centre , single-blind , placebo-controlled , parallel-group , dose-escalation study , 48 subjects ( aged 60 - 76 years ) were r and omized to receive a single oral dose of 30 , 40 or 50 mg of rivaroxaban or placebo . RESULTS Rivaroxaban was absorbed rapidly , reaching peak plasma concentration ( C(max ) ) 4 h after dosing in all groups . Bioavailability , in terms of the area under the plasma concentration-time curve ( AUC ) and C(max ) , increased slightly ( less than dose proportionally ) after administration of rivaroxaban 40 mg compared with 30 mg , but was not increased further with rivaroxaban 50 mg . Rivaroxaban  pharmacodynamic effects ( inhibition of FXa activity and prolongation of prothrombin time , activated partial thromboplastin time and HepTest ) all showed a similar pattern , with maximum inhibition of FXa activity increasing from 68 % after rivaroxaban 30 mg to 75 % after 40 mg and no further increase with the 50 mg dose . Most adverse events were mild ; observed rates were less than placebo for the 30 and 40 mg dose groups , and similar to placebo for 50 mg . No differences were found between male and female subjects . Effects of rivaroxaban doses above 50 mg were not investigated in this study . CONCLUSIONS Each single dose of rivaroxaban was well tolerated , with predictable pharmacokinetics and pharmacodynamics at doses up to 40 mg , and provided effective anticoagulation in healthy elderly subjects . Adverse events were somewhat elevated in 
    Output:
    
Results Apixaban , rivaroxaban and dabigatran have been found to be either non-inferior or superior to enoxaparin in prophylaxis of venous thromboembolism in knee and hip replacement with similar bleeding risk , superior to warfarin for stroke prevention in atrial fibrillation with significant reduction in the risk of major bleeding , non-inferior to aspirin for reducing cardiovascular death and stroke in acute coronary syndrome with significant increase in the risk of major bleed .
Rivaroxaban and dabigatran are also superior to the conventional agents in the management of symptomatic venous thromboembolism .
However , compared to enoxaparin , apixaban and rivaroxaban use lead to significantly increased bleeding risk in medically ill patients .
Conclusion Considering their pharmacological properties , their efficacy and bleeding complications , the new oral agents offer a net favourable clinical profile in orthopedic surgery , atrial fibrillation , acute coronary syndrome and increase the risk of bleeding in critically ill patients .