***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: Edoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism ( VTE ) in Japan . The objectives of this analysis were to characterise the population pharmacokinetics ( PK ) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement ( THR ) . A total of 1,795 subjects from a phase IIb study , 10 phase I studies , and three phase IIa studies were included in the PK analysis . The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study . Edoxaban disposition in healthy and post-surgical patients was well-described with a linear , two-compartment model . Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery . The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates . The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified . These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding This is a clinical safety , tolerability , pharmacokinetics ( PK ) , and pharmacodynamics ( PD ) study of a single ascending dose ( SAD ) and a multiple ascending dose ( MAD ) of the oral direct factor Xa inhibitor edoxaban in healthy males . The placebo-controlled , single-blind , r and omized , 2-part study consists of a SAD arm with 85 subjects ( 10 , 30 , 60 , 90 , 120 , 150 mg ) and a MAD arm with 36 subjects ( 90 mg daily , 60 mg twice daily , 120 mg daily ) . Effects of food and formulation ( tablet vs solution ) are assessed in a crossover sub study . In the SAD , doses are well tolerated up to 150 mg . Exposure is proportional to dose . PK profiles are consistent across dose with rapid absorption , biphasic elimination , and terminal elimination half-life of 5.8 to 10.7 hours . In the MAD , mean accumulation after daily dosing is 1.10 to 1.13 and consistent with elimination half-life of 8.75 to 10.4 hours . Intrasubject variability ranges from 12 % to 17 % for area under the curve . In general , plasma edoxaban concentrations are linearly correlated with coagulation parameters . Edoxaban is safe and well tolerated with no dose-dependent increases in adverse events . It is concluded that single and multiple doses of edoxaban are safe and well tolerated up to 150 mg with predictable PK and PD profiles BACKGROUND The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism . METHODS In a r and omized , double-blind , noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days ( interquartile range , 8 to 11 ) , we compared oral dabigatran , administered at a dose of 150 mg twice daily , with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0 . The primary outcome was the 6-month incidence of recurrent symptomatic , objective ly confirmed venous thromboembolism and related deaths . Safety end points included bleeding events , acute coronary syndromes , other adverse events , and results of liver-function tests . RESULTS A total of 30 of the 1274 patients r and omly assigned to receive dabigatran ( 2.4 % ) , as compared with 27 of the 1265 patients r and omly assigned to warfarin ( 2.1 % ) , had recurrent venous thromboembolism ; the difference in risk was 0.4 percentage points ( 95 % confidence interval [ CI ] , -0.8 to 1.5 ; P<0.001 for the prespecified noninferiority margin ) . The hazard ratio with dabigatran was 1.10 ( 95 % CI , 0.65 to 1.84 ) . Major bleeding episodes occurred in 20 patients assigned to dabigatran ( 1.6 % ) and in 24 patients assigned to warfarin ( 1.9 % ) ( hazard ratio with dabigatran , 0.82 ; 95 % CI , 0.45 to 1.48 ) , and episodes of any bleeding were observed in 205 patients assigned to dabigatran ( 16.1 % ) and 277 patients assigned to warfarin ( 21.9 % ; hazard ratio with dabigatran , 0.71 ; 95 % CI , 0.59 to 0.85 ) . The numbers of deaths , acute coronary syndromes , and abnormal liver-function tests were similar in the two groups . Adverse events leading to discontinuation of the study drug occurred in 9.0 % of patients assigned to dabigatran and in 6.8 % of patients assigned to warfarin ( P=0.05 ) . CONCLUSIONS For the treatment of acute venous thromboembolism , a fixed dose of dabigatran is as effective as warfarin , has a safety profile that is similar to that of warfarin , and does not require laboratory monitoring . ( Clinical Trials.gov number , NCT00291330 . Background — Selectivity , titratability , rapidity of onset , and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety . A novel anticoagulation system ( REG1 , Regado Biosciences ) , developed using a protein-binding oligonucleotide to factor IXa ( drug , RB006 ) and its complementary oligonucleotide antidote ( RB007 ) , was evaluated in healthy volunteers . The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study . Methods and Results — Regado 1a was a subject-blinded , dose-escalation , placebo-controlled study that r and omized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo . Pharmacodynamic sample s were collected serially . Subject characteristics were the following : median age , 32 years ( interquartile range , 23 to 39 years ) ; female gender , 35 % ; and median weight , 79 kg ( interquartile range , 70 to 87 kg ) . No significant differences were found in median hemoglobin , platelet , creatinine , or liver function studies . There were no significant bleeding signals associated with RB006 , and overall , both drug and antidote were well tolerated . One serious adverse event , an episode of transient encephalopathy , occurred in a subject receiving the low intermediate dose of RB006 . The subject 's symptoms resolved rapidly , and no further sequelae occurred . A predictable dose-pharmacodynamic response , reflected in activated partial thromboplastin time measurements , was seen after administration of the bolus of drug , with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug ( correlation coefficient , 0.725 ; P<0.001 ) . In subjects treated with drug , antidote administration reversed the pharmacological activity of the drug , with a rapid ( mean time , 1 to 5 minutes across all dose levels ) and sustained return of activated partial thromboplastin time to within the normal range . The activated clotting time followed a similar anticoagulant response and reversal pattern . As anticipated , prothrombin time remained unchanged compared with baseline . Conclusions — These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system . The findings contribute to an emerging platform of selective , actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations BACKGROUND After hip replacement surgery , prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism . Our aim was to assess the oral , direct thrombin inhibitor dabigatran etexilate for such prophylaxis . METHODS In this double-blind study , we r and omised 3494 patients undergoing total hip replacement to treatment for 28 - 35 days with dabigatran etexilate 220 mg ( n=1157 ) or 150 mg ( 1174 ) once daily , starting with a half-dose 1 - 4 h after surgery ,  or subcutaneous enoxaparin  40 mg once  daily  ( 1162 ) , starting the evening before surgery . The primary efficacy outcome was the composite of total venous thromboembolism ( venographic or symptomatic ) and death from all causes during treatment . On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo , the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7 % . Efficacy analyses were done by modified intention to treat . This trial is registered with Clinical Trials.gov , number NCT00168818 . FINDINGS Median treatment duration was 33 days . 880 patients in the dabigatran etexilate 220 mg group , 874 in the dabigatran etexilate  150 mg group , and 897 in the enoxaparin group were available for the primary efficacy outcome analysis ; the main reasons for exclusion in all three groups were the lack of adequate venographic data . The primary efficacy outcome occurred in 60 ( 6.7 % ) of 897 individuals in the enoxaparin group versus 53 ( 6.0 % ) of 880 patients in the dabigatran etexilate 220 mg group ( absolute difference -0.7 % , 95 % CI -2.9 to 1.6 % ) and 75 ( 8.6 % ) of 874 people in the 150 mg group ( 1.9 % , -0.6 to 4.4 % ) . Both doses were thus non-inferior to enoxaparin . There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin ( p=0.44 for 220 mg , p=0.60 for 150 mg ) . The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups . INTERPRETATION Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of  venous thromboembolism after total hip replacement surgery , with a similar safety profile Betrixaban is an oral direct inhibitor of factor Xa ( FXa ) being developed for the prevention of venous thromboembolism ( VTE ) . Its antithrombotic effects had not been previously tested in patients . This exploratory clinical trial in the US and Canada r and omized 215 patients undergoing elective total knee replacement ( TKR ) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o . bid or enoxaparin 30 mg s.c . q12h , respectively , for 10 - 14 days . The betrixaban dosage was blinded , but enoxaparin was not . Primary efficacy outcome was the incidence of VTE , consisting of deep-vein thrombosis ( DVT ) on m and atory unilateral ( operated leg ) venography , symptomatic proximal DVT , or pulmonary embolism ( PE ) through Day 10 - 14 . Safety outcomes included major and clinical ly significant non-major bleeds through 48 h after treatment . All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee . Of 214 treated patients , 175 ( 82 % ) were evaluable for primary efficacy . VTE incidence was 14/70 ( 20 % ; 95 % CI : 11 , 31 ) for betrixaban 15 mg , 10/65 ( 15 % ; 95 % CI : 8 , 27 ) for betrixaban 40 mg , and 4/40 ( 10 % ; 95 % CI : 3 , 24 ) for enoxaparin .  No bleeds were reported for betrixaban 15 mg , 2 ( 2.4 % ) clinical ly significant non-major bleeds with betrixaban 40 mg , and one ( 2.3 % ) major and two ( 4.6 % ) clinical ly significant non-major bleeds with enoxaparin . A dose- and concentration-dependent effect of betrixaban  on inhibition of thrombin generation and anti-Xa levels was observed . Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied BACKGROUND The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain . We 
    Output:
    
Of the agents in development , edoxaban holds the most promise due to robust data supporting its clinical benefit with a similar bleeding risk to currently approved agents .