***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 Warfarin , which requires coagulation monitoring , is associated with relatively high rates of thromboembolism despite providing adequate prophylaxis . This study compared an oral direct thrombin inhibitor , ximelagatran , with warfarin in order to evaluate the safety and efficacy of the medication for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty . METHODS Following surgery , patients were r and omly assigned to fixed-dose oral ximelagatran ( 36 mg twice daily ) or warfarin ( target international normalized ratio , 2.5 ) , both administered for seven to twelve days in a double-blind , double-dummy design . Warfarin was initiated on the evening of the day of surgery , and ximelagatran , on the morning after surgery . The primary efficacy end point was the incidence of asymptomatic deep-vein thrombosis determined by bilateral venography , objective ly confirmed symptomatic deep-vein thrombosis or pulmonary embolism , and death from all causes during treatment . RESULTS Adequate venograms or confirmed symptomatic events ( efficacy population ) were obtained for 1949 patients .  Venous thromboembolism and death from all causes occurred in 22.5 % ( 221 ) of 982 ximelagatran-treated patients and in 31.9 % ( 308 ) of 967 warfarin-treated patients ( p < 0.001 ) . Proximal deep-vein thrombosis and pulmonary embolism were observed in 3.1 % ( thirty ) and 0.2 % , respectively , of the patients in the ximelagatran group and in 3.4 % ( thirty-three ) and 0.4 % , respectively , of the patients in the warfarin group . The six deaths from all causes included 0.3 % ( four ) of the ximelagatran-treated patients and 0.2 % ( two ) of the warfarin-treated patients . Major bleeding was noted in 1 % ( twelve ) of the ximelagatran-treated patients and in 0.4 % ( five ) of the warfarin-treated patients ( p = 0.09 ) . CONCLUSIONS Oral ximelagatran ( 36 mg twice daily ) , administered without coagulation monitoring or dose adjustment and started the day after total knee arthroplasty , demonstrates superior efficacy compared with warfarin prophylaxis , with no wound complications and no significant difference with respect to bleeding events , although the rate of major bleeding events was greater with ximelagatran than with warfarin . LEVEL OF EVIDENCE Therapeutic Level BACKGROUND YM150 , a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism ( VTE ) , a well-known risk after orthopaedic surgery . OBJECTIVES To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study . PATIENTS / METHODS Patients ( 174 ) undergoing hip replacement surgery were r and omized per cohort to oral once daily YM150 or subcutaneous enoxaparin ( 40 mg daily ) in a 4:1 ratio for 7 - 10 days treatment . The YM150 doses were 3 , 10 , 30 and 60 mg by sequential four-dose escalation cohorts . The primary endpoint was major and /or clinical ly relevant non-major bleeding . The incidence of VTE was defined as a composite of verified symptomatic events and /or positive findings at bilateral venography on the last treatment day . An independent adjudication committee evaluated blindly the outcomes of the open-label study . RESULTS No major and three clinical ly relevant non-major bleeds were reported , 1 ( 2.9 % ; 95 % CI , 0.1 - 15.1 ) in the 3 mg and 2 ( 5.7 % ; 95 % CI , 1.0 - 18.8 ) in the 10 mg YM150 dose groups . Of 147 patients ( 84 % ) with an evaluable venogram , VTE was observed in 51.9 % ( 95 % CI , 31.9 - 71.4 ) , 38.7 % ( 95 % CI , 22.6 - 57.0 ) , 22.6 % ( 95 % CI , 9.7 - 39.4 ) , and 18.5 % ( 95 % CI , 7.5 - 36.5 ) in the YM150 dose groups 3 , 10 , 30 and 60 mg , respectively . A significant YM150 dose-related trend in VTE incidence was found ( P=0.006 ) . VTE with enoxaparin  was 38.7 % ( 95 % CI , 22.6 - 57.0 ) . CONCLUSIONS YM150 , 10 - 60 mg daily , starting 6 - 10 h after primary hip replacement , was shown to be safe , well tolerated and effective AIM The efficacy and safety of the new oral , direct and selective thrombin inhibitor Ximelagatran and its active form Melagatran was analysed in patients undergoing total hip or knee replacement . METHODS AND PATIENTS Methro II , a r and omised , double-blind controlled dose-finding study , involved 1876 patients .  Melagatran ( 1 , 1.5 , 2.25 or 3 mg ; twice daily ; start : immediately before surgery ) was given subcutaneously , followed by orally administered Ximelagatran ( 8 , 12 , 18 or 24 mg , twice daily , day after surgery ) and compared to subcutaneously administered dalteparin ( 5000 IE , once daily ) . Methro III was a r and omised , double blind controlled study involving 2788 patients . The fixed dose of 3 mg Melagatran was given ( start : 4 - 12 hours postoperatively ) followed by oral Ximelagatran ( 24 mg , twice daily , day after surgery ) compared to subcutaneous enoxaparin ( 40 mg , once daily ) . In both studies , dalteparin or enoxaparin was applied at the evening before operation ; the treatment lasted 8 to 11 days . A bilateral venography was performed at the last day of treatment . RESULTS In the Methro II study , 1270 patients underwent total hip , 606 total knee replacement . In both groups the thromboembolism rate was reduced depending on the dose of Ximelagatran/Melagatran . Compared to dalteparin , it was significantly lower for the Ximelagatran/Melagatran group with the highest dose . In the Methro III study 1923 patients underwent a total hip , 865 a total knee replacement . The thromboembolism rate was 31 % for the Ximelagatran/Melagatran group compared to 27 % for the enoxaparin group . In both studies blood loss and transfusion requirement were in the same range as with low weight molecular heparins . CONCLUSIONS A fixed subcutaneously given dose of Melagatran , followed by orally administered Ximelagatran is effective and well tolerated as prophylaxis against venous thromboembolism BACKGROUND Heparin-induced thrombocytopenia ( HIT ) is an intensely prothrombotic syndrome managed by discontinuation of heparin therapy and substitution of an alternative inhibitor of thrombin . We describe our experience with argatroban , a direct thrombin inhibitor , in patients with HIT or HIT with thrombosis ( HITTS ) . METHODS In this multicenter , nonr and omized prospect i ve study , 418 patients with HIT were administered  intravenous argatroban , 2 micro g/kg per minute , adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times the baseline value for a mean of 5 to 7 days . Comparisons were made with a historical control cohort ( n = 185 ) . The prospect ively defined , primary efficacy end point was a composite of all-cause death , all-cause amputation , or new thrombosis in 37 days . Other end points included the components of the composite , death due to thrombosis , increased platelet count , and bleeding . RESULTS In the HIT arm , the composite end point was significantly reduced in argatroban-treated patients vs controls ( 28.0 % vs 38.8 % ; P = .04 ) . In the HITTS arm , the composite end point occurred in 41.5 % of argatroban-treated patients vs 56.5 % of controls ( P = .07 ) . By time-to-event analysis of the composite end point , argatroban therapy was significantly better than historical control therapy in HIT ( P = .02 ) and HITTS ( P = .008 ) . Argatroban therapy also significantly reduced new thrombosis in HIT and HITTS and death due to thrombosis in HITTS . There were no significant between-group differences in all-cause death or amputation . Platelet counts recovered more rapidly in argatroban-treated patients than in controls . Bleeding rates were similar between groups . CONCLUSION Argatroban therapy , compared with historical control , improves outcomes , particularly new thrombosis and death due to thrombosis , in patients with heparin-induced thrombocytopenia Background — Rivaroxaban ( BAY 59 - 7939)—an oral , direct Factor Xa inhibitor — could be an alternative to heparins and warfarin for the prevention and treatment of thromboembolic disorders . Methods and Results — This r and omized , double-blind , double-dummy , active-comparator – controlled , multinational , dose-ranging study assessed the efficacy and safety of once-daily rivaroxaban relative to enoxaparin for prevention of venous thromboembolism in patients undergoing elective total hip replacement . Patients ( n=873 ) were r and omized to once-daily oral rivaroxaban doses of 5 , 10 , 20 , 30 , or 40 mg ( initiated 6 to 8 hours after surgery ) or a once-daily subcutaneous enoxaparin dose of 40 mg ( given the evening before and ≥6 hours after surgery ) . Study drugs were continued for an additional 5 to 9 days ; m and atory bilateral venography was performed the following day . The primary end point ( composite of any deep vein thrombosis , objective ly confirmed pulmonary embolism , and all-cause mortality ) was observed in 14.9 % , 10.6 % , 8.5 % , 13.5 % , 6.4 % , and 25.2 % of patients receiving 5 , 10 , 20 , 30 , and 40 mg rivaroxaban , and 40 mg enoxaparin , respectively ( n=618 , per- protocol population ) . No significant dose – response relationship was found for efficacy ( P=0.0852 ) . Major postoperative bleeding was observed in 2.3 % , 0.7 % , 4.3 % , 4.9 % , 5.1 % , and 1.9 % of patients receiving 5 , 10 , 20 , 30 , and 40 mg rivaroxaban , and 40 mg enoxaparin , respectively ( n=845 , safety population ) , representing a significant dose – response relationship ( P=0.0391 ) . Conclusions — Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total hip replacement , with the convenience of once-daily oral dosing and without the need for coagulation monitoring . When both efficacy and safety are considered , these results suggest that 10 mg rivaroxaban once daily should be investigated in phase III studies BACKGROUND For many patients with venous thromboembolism , secondary prevention with vitamin K antagonists is not extended beyond six months , since the risk of recurrence may be outweighed by the risk of major bleeding . METHODS In a double-blind , multicenter trial , we r and omly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran ( 24 mg ) or placebo , taken twice daily , for 18 months without monitoring of coagulation . At base line , bilateral ultrasonography of the legs and perfusion lung scanning were performed . RESULTS Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed . The occurrence of the primary end point , symptomatic recurrent venous thromboembolism , was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo ( hazard ratio , 0.16 ; 95 percent confidence interval , 0.09 to 0.30 ; P<0.001 ) . Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group , and bleeding occurred in 134 patients and 111 patients , respectively ( hazard ratio , 1.19 ; 95 percent confidence interval , 0.93 to 1.53 ; P=0.17 ) . The incidence of major hemorrhage was low ( six events in the ximelagatran group and five in the placebo group ) , and none of 
    Output:
    
Therefore , the effect of the DTIs compared with LMWH appears to be influenced by the time of initiation of coagulation more than the effect of the drug itself .
Direct thrombin inhibitors are as effective in the prevention of major venous thromboembolism in THR or TKR as LMWH and vitamin K antagonists .
However , they show higher mortality and cause more bleeding than LMWH .
No severe hepatic complications were reported in the analysed studies .
Use of ximelagatran is not recommended for VTE prevention in patients who have undergone orthopedic surgery .