***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 In ROCKET AF ( Rivaroxaban Once-Daily , Oral , Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ) , a large r and omized , clinical trial , rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation . OBJECTIVE To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)-naive and VKA-experienced patients . DESIGN Prespecified subgroup analysis . ( Clinical Trials.gov : NCT00403767 ) . SETTING Global . PATIENTS 14,264 persons with atrial fibrillation . MEASUREMENTS Interaction of the relative treatment effect of  rivaroxaban and warfarin  on stroke or systemic embolism among VKA-naive and VKA-experienced patients . RESULTS Overall , 7897 ( 55.4 % ) patients were VKA-experienced and 6367 ( 44.6 % ) were VKA-naive . The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent : Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients ( hazard ratio [ HR ] , 0.81 [ 95 % CI , 0.64 to 1.03 ] ) and 1.98 versus 2.09 for VKA-experienced patients ( HR , 0.94 [ CI , 0.75 to 1.18 ] ; interaction P = 0.36 ) . During the first 7 days , rivaroxaban was associated with more bleeding than warfarin ( HR in VKA-naive patients , 5.83 [ CI , 3.25 to 10.44 ] , and in VKA-experienced patients , 6.66 [ CI , 3.83 to 11.58 ] ; interaction P = 0.53 ) . After 30 days , rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients ( HR , 0.84 [ CI , 0.74 to 0.95 ] ) and similar bleeding in VKA-experienced patients ( HR , 1.06 [ CI , 0.96 to 1.17 ] ; interaction P = 0.003 ) . LIMITATION The trial was not design ed to detect differences in these subgroups . CONCLUSION The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial . There were more bleeding events within 7 days of study drug initiation with rivaroxaban , but after 30 days , rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients . This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy . PRIMARY FUNDING SOURCE Johnson & Johnson and Bayer HealthCare 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 Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects . The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known . METHODS We conducted a r and omized , double-blind , double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation ( median follow-up , 2.8 years ) . The primary efficacy end point was stroke or systemic embolism . Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period . The principal safety end point was major bleeding . RESULTS The annualized rate of the primary end point during treatment was 1.50 % with warfarin ( median time in the therapeutic range , 68.4 % ) , as compared with 1.18 % with high-dose edoxaban ( hazard ratio , 0.79 ; 97.5 % confidence interval [ CI ] , 0.63 to 0.99 ; P<0.001 for noninferiority ) and 1.61 % with low-dose edoxaban ( hazard ratio , 1.07 ; 97.5 % CI , 0.87 to 1.31 ; P=0.005 for noninferiority ) . In the intention-to-treat analysis , there was a trend favoring high-dose edoxaban versus warfarin ( hazard ratio , 0.87 ; 97.5 % CI , 0.73 to 1.04 ; P=0.08 ) and an unfavorable trend with low-dose edoxaban versus warfarin ( hazard ratio , 1.13 ; 97.5 % CI , 0.96 to 1.34 ; P=0.10 ) . The annualized rate of major bleeding was 3.43 % with warfarin versus 2.75 % with high-dose edoxaban ( hazard ratio , 0.80 ; 95 % CI , 0.71 to 0.91 ; P<0.001 ) and 1.61 % with low-dose edoxaban ( hazard ratio , 0.47 ; 95 % CI , 0.41 to 0.55 ; P<0.001 ) . The corresponding annualized rates of death from cardiovascular causes were 3.17 % versus 2.74 % ( hazard ratio , 0.86 ; 95 % CI , 0.77 to 0.97 ; P=0.01 ) , and 2.71 % ( hazard ratio , 0.85 ; 95 % CI , 0.76 to 0.96 ; P=0.008 ) , and the corresponding rates of the key secondary end point ( a composite of stroke , systemic embolism , or death from cardiovascular causes ) were 4.43 % versus 3.85 % ( hazard ratio , 0.87 ; 95 % CI , 0.78 to 0.96 ; P=0.005 ) , and 4.23 % ( hazard ratio , 0.95 ; 95 % CI , 0.86 to 1.05 ; P=0.32 ) . CONCLUSIONS Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes . ( Funded by Daiichi Sankyo Pharma Development ; ENGAGE AF-TIMI 48 Clinical Trials.gov number , NCT00781391 . ) BACKGROUND Stroke and systemic thromboembolism are serious problems for patients with atrial fibrillation ( AF ) , but their incidence can be substantially reduced by appropriate anticoagulation . Bleeding is the major complication of anticoagulant treatment , and the relative risks for bleeding vs stroke must be considered when starting anticoagulation . METHODS The AFFIRM trial included patients with AF and at least one risk factor for stroke , r and omly assigning them to either a rate-control or rhythm-control strategy . All patients were initially treated with warfarin . The incidence of protocol -defined major and minor bleeding was documented during follow-up . Variables associated with bleeding were determined using a Cox proportional hazards model , using baseline and time-dependent covariates . RESULTS The 4060 patients in the AFFIRM trial were followed for an average of 3.5 years . Major bleeding occurred in 260 patients , an annual incidence of approximately 2 % per year , with no significant difference between the rate-control and rhythm-control groups . Increased age , heart failure , hepatic or renal disease , diabetes , first AF episode , warfarin use , and aspirin use were significantly associated with major bleeding . Minor bleeding was common in both treatment arms , with 738 patients reporting this problem in one or more visits . CONCLUSIONS Bleeding is a significant problem that complicates management of patients with AF . Risk factors for bleeding can be identified , and knowledge of these risk factors can be used to plan therapy CONTEXT In patients with nonvalvular atrial fibrillation , warfarin prevents ischemic stroke , but dose adjustment , coagulation monitoring , and bleeding limit its use . OBJECTIVE To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , multicenter trial ( 2000 - 2001 ) conducted at 409 North American sites , involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors . INTERVENTIONS Adjusted-dose warfarin ( aim ing for an international normalized ratio [ INR ] 2.0 to 3.0 ) or fixed-dose oral ximelagatran , 36 mg twice daily . MAIN OUTCOME MEASURES The primary end point was all strokes ( ischemic or hemorrhagic ) and systemic embolic events . The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0 % per year according to the intention-to-treat model . RESULTS During 6405 patient-years ( mean 20 months ) of follow-up , 88 patients experienced primary events . The mean ( SD ) INR with warfarin ( 2.4 [ 0.8 ] ) was within target during 68 % of the treatment period . The primary event rate with ximelagatran was 1.6 % per year and with warfarin was 1.2 % per year ( absolute difference , 0.45 % per year ; 95 % confidence interval , -0.13 % to 1.03 % per year ; P<.001 for the predefined noninferiority hypothesis ) . When all-cause mortality was included in addition to stroke and systemic embolic events , the rate difference was 0.10 % per year ( 95 % confidence interval , -0.97 % to 1.2 % per year ; P = .86 ) . There was no difference between treatment groups in rates of major bleeding , but total bleeding ( major and minor ) was lower with ximelagatran ( 37 % vs 47 % per year ; 95 % confidence interval for the difference , -14 % to -6.0 % per year ; P<.001 ) . Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6. 
    Output:
    
In conclusion , use of dabigatran in prior VKA users in clinical practice was associated with a slightly increased risk of arterial thromboembolism and gastrointestinal bleeding , but a decreased risk of intracranial bleeding .