***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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    ***EXAMPLES*** 
    Input: 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 Summary Of the new direct oral anticoagulants , direct factor Xa inhibitors are limited by the absence of a proven reversal agent . We assessed the safety , tolerability and impact on anticoagulation reversal of ciraparantag ( PER977 ) alone and following a 60 mg dose of the FXa inhibitor edoxaban . Escalating , single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind , placebo-controlled fashion to healthy subjects . Serial assessment s of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed . Eighty male subjects completed the study .  Following edoxaban ( 60 mg ) , a single IV dose of ciraparantag ( 100 to 300 mg ) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours . Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis . Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag . Renal excretion of ciraparantag metabolite was the main elimination route . There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer , prothrombin fragments 1.2 , and tissue factor pathway inhibitor levels . In conclusion , ciraparantag in healthy subjects is safe and well tolerated with minor , non-dose limiting adverse events . Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours . Institution where the work was performed : Duke University Clinical Research Unit , Duke University Medical Center , Durham , NC INTRODUCTION This phase I , open-label , multiple-dose , two-treatment study assessed the relationship between edoxaban equivalent concentration derived from an anti-FXa assay with the summed concentration of edoxaban and its active metabolite , M-4 , as assessed by liquid chromatography coupled with t and em mass spectrometry ( LC/MS/MS ) . This study also assessed the relationship between edoxaban plasma concentrations assessed by LC/MS/MS in sodium citrate and lithium heparin tubes . MATERIAL S AND METHODS Healthy volunteers were r and omized to receive once-daily edoxaban 60 mg or 90 mg for 5days ( 15 participants per treatment group ) . Serial blood sample s were collected for analysis by LC/MS/MS and by the anti-FXa assay . Edoxaban equivalent levels were assessed using a commercially available anti-FXa activity assay with an edoxaban-specific setup . RESULTS AND CONCLUSIONS The day 5 concentration estimates were significantly correlated between the 2 assays ( P<0.0001 for both edoxaban doses ) . The geometric least squares mean ( GLSM ) ratio ( 90 % confidence interval ) for edoxaban equivalent concentrations vs edoxaban + M-4 concentrations was 114.3 % ( 108.2 - 120.8 ) for edoxaban 60 mg ( P<0.0001 ) and 113.0 % ( 107.1 - 119.2 ) for edoxaban 90 mg ( P=0.0002 ) . The GLSM ratio for edoxaban concentrations in sodium citrate vs lithium heparin tubes for 60-mg and 90-mg edoxaban doses were 82.8 % ( 78.5 - 87.3 ) and 83.9 % ( 79.1 - 89.0 ) , respectively . In this study , an anti-FXa chromogenic assay with edoxaban-specific calibrators and controls demonstrated good accuracy in estimating edoxaban concentrations across a wide range of concentrations relative to LC/MS/MS at steady state following the administration of once-daily edoxaban for 5days Purpose Real-world data on the use of rivaroxaban in the perioperative period in patients undergoing major orthopedic surgery are limited . Subsets of data from the Phase IV , non-interventional XAMOS study were analyzed to explore the potential influence of timing of the first thrombo prophylactic dose , type of anesthesia , and concomitant mechanical prophylaxis on clinical outcomes in patients undergoing major orthopedic surgery in routine clinical practice . Patients and methods In XAMOS , 8,778 patients received rivaroxaban ( 10 mg once daily ) and 8,635 received st and ard-of-care ( SOC ) pharmacological prophylaxis  ( safety population ) . Crude incidences of symptomatic thromboembolic and treatment-emergent bleeding events were analyzed according to timing of the first postoperative thromboprophylactic dose , use of general or neuraxial anesthesia , and use of mechanical prophylaxis with pharmacological thromboprophylaxis . Results In the rivaroxaban group , the incidences of symptomatic thromboembolic events were 0.7 % , 1.0 % , and 0.7 % in patients receiving the first thromboprophylactic dose at ≤6 hours , > 6 hours to ≤10 hours , and > 10 hours to ≤24 hours after surgery , respectively . In the SOC group , the incidence of symptomatic thromboembolic events was slightly higher when the postoperative dose was given at > 10 hours to ≤24 hours ( 1.8 % vs 1.1 % at ≤6 hours and 1.3 % at > 6 hours to ≤10 hours ) . The antithrombotic effect of rivaroxaban was maintained in comparison to the SOC group . The incidence of major bleeding ( RECORD trial definition ) was low and similar between the two treatment groups and was not influenced by timing of the first thromboprophylactic dose . Neuraxial anesthesia was used more than any other form of anesthesia for both hip and knee surgery ; the effectiveness of rivaroxaban was not influenced by the type of anesthesia used . No spinal hematomas were reported in patients receiving neuraxial anesthesia in either treatment group . Use of mechanical thromboprophylaxis in addition to rivaroxaban or SOC pharmacological prophylaxis did not reduce the risk of thromboembolic events further . Conclusion The effectiveness and safety of rivaroxaban in patients undergoing major orthopedic surgery in routine clinical practice were maintained irrespective of timing of the first postoperative dose within 24 hours after surgery , the type of anesthesia , and the additional use of mechanical thromboprophylaxis 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 . Aims VENTURE-AF is the first prospect i ve r and omized trial of uninterrupted rivaroxaban and vitamin K antagonists ( VKAs ) in patients with non-valvular atrial fibrillation ( NVAF ) undergoing catheter ablation ( CA ) . Methods and results Trial size was administratively set at 250 , the protocol -specified target . Events were independently and blindly adjudicated . We r and omly assigned 248 NVAF patients  to uninterrupted rivaroxaban ( 20 mg once-daily ) or to an uninterrupted VKA prior to CA and for 4 weeks afterwards . The primary endpoint was major bleeding events after CA . Secondary endpoints included thromboembolic events ( composite of stroke , systemic embolism , myocardial infa rct ion , and vascular death ) and other bleeding or procedure-attributable events . Patients were 59.5 ± 10 years of age , 71 % male , 74 % paroxysmal AF , and had a CHA2DS2-VASc score of 1.6 .  The average total heparin dose used to manage activated clotting time ( ACT ) was slightly higher ( 13 871 vs. 10 964 units ; P < 0.001 ) and the mean ACT level attained slightly lower ( 302 vs. 332 s ; P < 0.001 ) in rivaroxaban and VKA arms , respectively . The incidence of major bleeding was low ( 0.4 % ; 1 major bleeding event ) . Similarly , thromboembolic events were low ( 0.8 % ; 1 ischemic stroke and 1 vascular death ) . All events occurred in the VKA arm and all after CA . The number of any adjudicated events ( 
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There is a paucity of high- quality data on the optimal timing of NOAC cessation and resumption in the perioperative period , particularly for patients who undergo procedures with high bleeding risk .
Conclusions and Relevance The anticoagulant effect of NOAC agents is predictable but not readily measurable in routine clinical practice .